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Multidrug Efflux Pumps in Bacteria and Efflux Pump Inhibitors

Pubblicato online: 24 Jul 2022
Volume & Edizione: AHEAD OF PRINT
Pagine: -
Ricevuto: 01 Mar 2022
Accettato: 01 May 2022
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Rivista
eISSN
2545-3149
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01 Mar 1961
Frequenza di pubblicazione
4 volte all'anno
Lingue
Inglese, Polacco
Introduction

Antimicrobial resistance (AMR) arises when micro-organisms develop strategies to evade antimicrobial agents, making them ineffective. AMR is a global threat to the public health system across the globe. According to a recent report from the WHO, drug-resistant diseases claim the lives of at least 700,000 individuals each year [1]. Due to the inappropriate dosage and use of current antimicrobials, many pathogens become multi-drug-resistant (MDR) [2]. It is generally assumed that resistance to antibiotics and other antimicrobials has developed due to selective pressures resulting from indiscriminate and inappropriate use. Increased antibiotic resistance has resulted in fewer treatment options for patients and increased morbidity and death. Due to this, we are now confronted with more acute diseases that require more intense treatment, relatively extended hospital stays and expensive hospitalization [3]. Bacteria can gain resistance through diverse mechanisms such as restricting drug uptake into the cell, altering a drug target, enzymatic degradation of a drug, and active efflux of a drug. The efflux mechanism involves the extrusion of drugs from the interior to the external environment by protein transporters called multidrug efflux pumps (EPs). An EP reduces the efficacy of antibiotics by preventing their intracellular accumulation. The efflux-mediated resistance is widespread in the bacteria [4]. Numerous studies have shown that EPs, such as AcrAB-TolC of Escherichia coli, MexAB-OprM of Pseudomonas aeruginosa, and AdeFGH of Acinetobacter baumanii help in biofilm formation, pathogenicity, stress tolerance, and quorum sensing (QS) [5,6,7,8]. The link between EPs and QS has been investigated in P. aeruginosa. Mutation in RND EP leads to the downregulation of QS-dependent LecA-Lux pathways, thereby increasing the expulsion of QS molecules and biofilm formation [9]. EPs can interact with host-derived antimicrobials such as bile salts, contributing to the virulence of enteric bacteria; the RND EP, AcrAB-TolC from E. coli is involved in the extrusion of bile salt, is a good example [10]. Other RND EPs, VexAB, VexCD, VexIJK, and VexGH, increase the pathogenicity of Vibrio cholerae by encoding the two major virulence factors: cholera toxin (CT) and toxin co-regulated pilus (TCP) [11]. This review will focus on the major classes of EPs identified in bacteria and discuss the newly identified EPIs.

Major classes of efflux pumps

The EPs are predominantly found in Gram-positive bacteria (GPB) such as Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Listeria monocytogenes and Gram-negative bacteria (GNB) including E. coli, A. baumanii, Klebsiella pneumoniae, Camphylobacter jejuni, P. aeruginosa, Neisseria gonorrheae and V. cholerae. EPs are energy-dependent as they expel toxic substrates against a concentration gradient. The EPs can be classified into two types based on their energy source. The primary EPs directly utilize energy from ATP hydrolysis, while the secondary EPs derive energy from the chemical gradients from protons or sodium ions. The GNB EPs are more complex than GPB EPs and possess tripartite assembly. They can expel a broad spectrum of antibiotics such as quinolones, β-lactams, and tetracycline [12,13,14,15]. Major efflux in GNBs are AcrAB-TolC efflux (E. coli), AcrAD-TolC and AcrEF-TolC (Salmonella enterica). KdeA, KmrA, KpnEP and EefABC in (K. pneumoniae), MexAB-OprM, MexJK-OprM, MexEF-OprN, MexXY-OprM, MexCD-OprJ and MexVW-OprM (P. aeruginosa), SsmE, SdeAB, SdeCDE, SdeXY, SmdAB and SmfY (Serratia marcescens) MarA and AcrAB (Yersinia pestis) CmeABC (C. jejuni) and AdeIJK, AdeABC and AdeFGH (A. baumanii) [16].

The EPs are classified into five families based on the number of membrane-spanning regions, sequence similarity, substrate specificity and energy source used by the pump and the types of molecules exported (Fig. 1).

Fig. 1

Schematic representation of five superfamilies of EPs found in bacteria

(ABC) ATP-Binding Cassette Superfamily [17]; (MFS) Major Facilitator Superfamily [18]; (MATE) Multidrug And Toxic Compound Extrusion Family [19]; (SMR) Small Multi-Drug Resistance Family [20]; (RND) Resistance-Nodulation-Division Superfamily [21].

ATP-binding cassette superfamily

ATP-binding cassette (ABC) transporters are a large superfamily that uses the energy released upon ATP hydrolysis to pump chemicals [22]. They function as influx and efflux proteins, transporting nutrients into cells and removing toxins and drugs from the cell. However, in Eukaryotes, ABC transporters behave as efflux proteins that protect the cell against toxins [23]. A distinguishing feature of ABC transporters is the presence of two transmembrane domains, which help in substrate translocation, and two cytoplasmic ATP-binding domains that generate energy by ATP hydrolysis to move the substrates across the membrane [24]. ABC transporters contain highly conserved motifs such as Walker A and Walker B motifs (binds to ATP) and LSGGQ/KQR (C-motif) [25]. LmrA (involved in the efflux of ethidium, rhodamine G, daunorubicin) was the first bacterial MDR ABC transporter reported and was identified in Lactococcus lactis [26]. A homolog of LmrA, named BmrA, was identified from Bacillus subtilis which expelled drugs such as Hoechst 33342, doxorubicin and 7-amino-actinomycin-D [27]. MacAB-TolC, initially identified as a tripartite pump, is involved in the efflux of macrolide antibiotics, protoporphyrin and heat-stable enterotoxins [28]. Similarly, DrrA (ATP binding) and DrrB (integral membrane protein) from Mycobacterium tuberculosis imparted resistance to doxorubicin and daunorubicin [29]. PatAB in S. pneumoniae is implicated in the efflux of several drugs, including fluoroquinolones [30]. EfrCD, an ABC transporter characterized in Enterococcus faecalis demonstrated enhanced sensitivity to several drugs, such as daunorubicin and doxorubicin [31]. SmrA is an ABC transporter identified in the nosocomial pathogen, Stenotrophomonas maltophilia, which conferred increased resistance to fluoroquinolones and tetracycline [32]. SmdAB, a multidrug efflux transporter, was identified in S. marcescens involved in the transport of antibiotics, norfloxacin and tetracycline [33]. A multidrug EP, VcaM, was identified in V. cholerae, conferring resistance to fluoroquinolones and tetracycline [34]. Recently, YddA was identified as an ABC-type multidrug transporter associated with exporting several substrates, including norfloxacin [35].

Major Facilitator Superfamily

Major Facilitator Superfamily (MFS) transporters are found in most living forms, including humans, and they transport many small compounds across the cell membranes [36]. The gene encoding the MFS transporters is present in high copy numbers. For example, E. coli K-12 likely has more than 70 transporters [37]. Unlike ABC transporters which are primary active transporters depending on ATP hydrolysis, MFS transporters are secondary active transporters moving smaller solute particles depending on the ion gradient created by active transporters [18]. The MFS transporters function as symport, antiport, or uniport and transport a wide range of compounds, including glucose, oligosaccharides, inositols, drugs, amino acids, and nucleosides. Structurally, MFS transporters are composed of 400–600 amino acids that fold into 12 or 14 transmembrane helices [38].

MdfA, an MDR EP identified in E. coli is involved in the transport of lipophilic compounds such as ethidium bromide, rhodamine, daunomycin, rifampin, tetracycline, and puromycin [39]. LmrP, a proton/drug anti-port pump from L. lactis is involved in the extrusion of lincosamide, streptogramin, and tetracycline [40]. Fluoro quinolones, biocides, dyes, quaternary ammonium compounds and antiseptics are substrates of NorA EP from S. aureus and Staphylococcus epidermis [41]. Bmr and Blt of B. subtilis, and QacA of S. aureus are other examples of MFS transporters in GPB [42]. MFS transporters are monomeric in GPB, whereas they possess tripartite assembly in GNB. Tripartite EmrAB-TolC and EmrKY-TolC of E. coli enable the transport of the substrates ie. thiolactomycin, cerulenin, nalidixic acid and nitroxolone across the outer and inner membranes of GNB [43, 44].

Multidrug and toxic compound extrusion family

Multidrug and toxic compound extrusion (MATE) family comprises active secondary transporters and contributes to MDR in V. cholerae and N. gonorrhoeae. MATE family of transporters pump a wide range of toxic compounds from mammalian and bacterial cells harnessing the proton motive force and cation gradient. Many toxic metabolites and antimicrobial drugs are transported across the membrane by the MATE family, contributing to multidrug tolerance [45]. The NorM transporters from V. cholerae and N. gonorrhoeae and DinF transporters from Pyrococcus furiosus and Bacillus halodurans are well characterized [46]. NorM from Vibrio parahaemolyticus can extrude antibiotics, norfloxacin and ciprofloxacin outside the cells energy-dependent [47]. All MATE EPs are frequently made up of 12 transmembrane helices except mammalian MATE transporters, containing one additional helix [48]. MDR EP of the MATE family, MepA, is responsible for the extrusion of norfloxacin, ciprofloxacin and tigecycline [49, 50]. Interestingly, human MATE transporters (hMATE1-K and hMATE2-K) contribute to the transport of drugs, such as cimetidine, metformin, procainamide, cephalexin, and acyclovir [51]. PmpM, a proton-drug anti-transporter belonging to MATE family, associated with extrusion of fluoroquinolones, was identified in P. aeruginosa [52].

Small multidrug resistance family

As their name suggests, SMR transporters are small (~12 kDa) proteins consisting of 100 to 140 amino acids and involved in transporting a variety of lipophilic compounds and antibiotics [53, 54]. A proton gradient or ATP-dependent mechanism drives the transport of the substrates across the membrane. All SMR transporter consists of 4 transmembrane helix with primarily α-helical structure [55]. EmrE is an SMR type transporter in E. coli exchanging H+ with ethidium and tetraphenylphosphonium compounds [56].The SMR transporters are further classified into three subclasses: the small multidrug pumps (SMP), suppressors of groEL mutation proteins (SUG), and paired small multidrug resistance proteins (PSMR) [54]. SMR proteins are encoded by bacterial chromosomes or plasmids and may be present in integrons. SMR transporters confera high level of resistance to several classes of antibiotics, such as β-lactams, cephalosporins co-trimoxazole, and a few aminoglycosides [39].

Resistance-Nodulation-Division Superfamily

The Resistance-Nodulation-Division (RND) efflux protein superfamily was initially identified as proteins related to Heavy Metal Resistance (Ralstonia metallidurans), Nodulation (Mesorhizobium loti) and Cell division (E. coli) [57]. AdeABC is the first characterized RND EP in A. baumannii, conferring multidrug resistance [58]. The components of AdeABC EP are adeA, adeB and adeC encoding membrane fusion proteins, multidrug transporter and outer membrane channel protein, respectively [59]. The adeABC is associated with the active extrusion of fluoroquinolones, tetracycline, macrolides and aminoglycosides [58]. The members of the RND family play a key role in conferring antibiotic resistance in GNB, whereas the MATE family is mainly concerned with resistance in GPB [60]. RND pumps are proton gradient dependent and possess a tripartite assembly with three subunits, an inner membrane protein (IMP), an outer-membrane protein (OMP), and a periplasmic membrane fusion protein (MFP) which connect the other two components. The AcrAB-TolC EP, a well-characterized RND pump, encompasses the outer-membrane channel TolC, the transporter AcrB in the inner membrane, and AcrA, a periplasmic component interacting with the TolC and AcrB. The crystal structure of AcrB confirmed that it is a homotrimer [61]. The AcrAB-TolC EP transports several compounds and imparts resistance to antibiotics [62]. Another well-studied RND transporter is MexA-MexB-OprM from P. aeruginosa, actively extruding tetracycline, norfloxacin, and chloramphenicol [63]. E. coli RND transporter, SecDF, is a proton-dependent protein translocation factor that functions as a protein exporter [64]. RND efflux system, VexB, VexD, VexK and VexH, identified in V. cholerae, exhibited resistance to bile salts and several antimicrobial agents [11].

Efflux pumps and their role in virulence and biofilm formation

It has been demonstrated that the efflux of several host-derived antimicrobials agents, such as bile salts, facilitates colonization and increases bacterial adaptation to the host digestive tract [65]. In E. coli, the RND EP, AcrAB-TolC, primarily involved in drug efflux, can also impart bile salt resistance [10]. Biofilms are complex microbial communities attached to several surfaces, including implanted devices such as urinary catheters. It is well-known that bacteria encased in biofilm show a greater degree of antibiotic resistance than planktonic cells. The relationship between antimicrobial tolerance of biofilm and EPs has been reported in several bacterial species [66]. For example, the antimicrobial tolerance of biofilms in P. aeruginosa increases due to the expression of the multidrug EPs MexAB-OprM and MexEF-OprN [67]. The upregulation of EPs affects the flagellar motility, which plays a crucial role in biofilm formation [68]. The deletion of genes encoding RND EP diminished the ability of biofilm formation in S. maltophilia and the retraction of flagellar formation [69]. Intriguingly, the upregulation of RND efflux causes inhibition of the type III secretion system in P. aeruginosa, which deliver bacterial toxins into the host cell, thus reducing the virulence [70].

AcrAB-TolC, MexAB-OprM, AdeFGH and AcrD are crucial in biofilm formation. Numerous studies have examined the relationship between EPs and biofilm formation [71,72,73]. Gene expression studies using microarrays have shown that efflux encoding genes, mdtF and lsrA are upregulated during biofilm formation and QS in E. coli [8]. Klebsiella sp. isolates exhibiting efflux activity formed strong biofilm [74]. A strong correlation exists between the overexpression of the AdeFGH EP and biofilm formation by clinical isolates of A. baumannii [6]. Further, efflux genes yihN and mdtO are overexpressed in E. coli biofilms and are involved in the efflux of glucose, a major constituent of the extracellular polymer matrix [75]. An MDR EP, YhcQ confer drug resistance in the E. coli biofilm, whereas TolC plays an important role in the adhesion and biofilm formation in enteroaggregative E. coli [66]. MexAB-OprM EP extruded tetracycline, chloramphenicol, quinolones and β-lactams in P. aeruginosa biofilms [76]. Correlation between biofilm formation, drug resistance, and efflux mechanism has been reported in P. aeruginosa recently. In addition, the occurance of such cases may be a major public health concern in the treatment of infections caused by the pathogen [77]. Several EP genes, ie. acrA, emrB, oqxA are overexpressed in K. pneumoniae biofilms [71]. Deletion of the bcr gene decreased the biofilm formation of P. mirabilis and reduced catheter blockage [78]. Similarly, deletion of EP encoding genes (acrB, acrD, acrEF, emrAB, macAB, mdfA, mdsABC, mdtABC, mdtK, and tolC) impaired biofilm formation in Salmonella enterica [79]. The EPs play an important role in Helicobacter pylori biofilm drug resistance. Studies have shown upregulation of EP encoding genes (kefB, hefA, yckJ, tetA, gln, crdB/hefG and ybhS) in biofilm compared to planktonic cells [80]. These data, taken together, strongly show a relationship between efflux activity and biofilm development.

Efflux Pump Inhibitors

Efflux abolition could be accomplished by various means: (i) controlling the expression of EPs (ii) discovering new antibacterial agents that do not act as substrates, (iii) identifying small molecules inhibiting the EPs or mimicking the substrates and subsequently blocking EP [15]. The Efflux Pump Inhibitors (EPIs) are molecules capable of inhibiting EPs and preventing the extrusion of foreign compounds. EPIs, inhibit EPs by one or more mechanisms mentioned above. The synergistic activity of EPI and the antibiotics can strengthen their efficacy against bacteria expressing EPs, as this might lead to an adequate accumulation of an antibiotic inside the cell. Eventhough several EPIs have been identified at the experimental level in recent years, none have been approved by the FDA and used therapeutically.

The relationship between EPs and biofilm formation is well understood, therefore, EPIs can also reduce biofilm formation. Several EPIs act as biofilm disruptors, e.g., the combinations of EPIs, thioridazine with Phenylalanine-arginine β-naphthylamide (PaβN) and thioridazine with 1-naphthylmethyl-piperazine (NMP) reduced 80–99% of biofilm formation in E. coli [81]. Biofilm inhibitors such as reserpine, linoleic acid, berberine and curcumin exhibited efflux inhibitory activity in K. pneumoniae [82]. EPIs can also act as adjuvants, e.g., PAβN and NMP can compete with levofloxacin for the binding site of RND pumps (MexAB, MexCD and MexEF) in P. aeruginosa and E. coli (AcrAB and AcrEF), thereby increasing the accumulation of levofloxacin [83, 84]. A competitive interaction between PAβN and polyamine potentiates the tetracycline concentration and abolishes biofilm formation in P. aeruginosa [85]. Other clinically approved drugs such as nilotinib, dihydroergotamine, ergoloid, azelastine, doxazosin and telmisartan are competitive inhibitors of ciprofloxacin [86]. Mahey et al., identified azoles as putative TetK EPI that reduced the S. aureus associated biofilm [87]. Fluoxetine and thioridazine drugs can strongly inhibit the biofilm-associated Bcr/CflA efflux system and swarming motility of Proteus mirabilis [88]. Quinazoline derivatives enhanced the inhibitory activity of chloramphenicol and nalidixic acid in EP over-expressing strains of Enterobacter aerogenes, P. aeruginosa and K. pneumonia [89]. Similarly, peptidomimetic EPI, PaβN, increases the antibacterial activity of levofloxacin and erythromycin in MexAB-OprM overexpressing clinical isolates of P. aeruginosa [90]. A novel EPI, conessine reduced the MIC of all antibiotics by 8-fold in MexAB-OprM overexpressed P. aeruginosa through competitive inhibition [91]. Carbonyl-cyanide 3-chlorophenylhydrazone (CCCP) is an important EPI that can disrupt the energy or ATP levels of bacteria (oxidative phosphorylation) and abolishes the efflux of various molecules. It could reverse the colistin resistance of GNB without affective tigecycline and carbapenem resistance [92]. In another study, CCCP showed synergism with ciprofloxacin, imipenem, gentamicin and cefepime in P. aeruginosa [93]. CCCP is a known proton motive force inhibitor of MexAB-OprM overexpressing P. aeruginosa biofilm [94]. Xanthone derivatives effectively inhibit specific EPs such as AcrAB-TolC in S. typhimurium and NorA in S. aureus [95]. Oliveira-Tintino et al., reported that 1,8 naphthyridines reduced the MIC of norfloxacin and ethidium bromide in NorA overexpressing S. aureus strains [96]. The calcium channel blocker verapamil, clinically used to treat cardiac disorders, can inhibit ATP-dependent multidrug resistant EPs and reverse the resistance of rifampicin, ofloxacin, streptomycin, and ethidium bromide in M. tuberculosis. Valinomycin is a potassium-specific EPI extracted from Streptomyces that targets the MFS and ABC EPs. They have been shown to inhibit the P55, an MFS EP that relies on the electrochemical gradient for the active efflux of substrates in M. tuberculosis [97]. The list of EPIs, their mechanism of action, origin and their corresponding target EPs are shown in Table 1.

List of Efflux Pump Inhibitors based on mechanism of action, origin, targets and substrates

Mechanism of action/Compounds EPIs Target EPs Bacteria Substrates References
1. Mechanism of Action
Energy Disruption CCCP-Carbonyl cyanide chlorophenyl hydrazone MFS- tetA, tetB H. pylori, Klebsiella spp. Tetracycline [98, 99]
Synthetic EPI- IITR08027 MATE- abeM E. coli, A. baumanii Fluoroquinolones [100]
PAβN RND- mexAB-oprM, mexCD-oprJ, mexEF-oprN P. aeruginosa LevofloxacinErythromycinStreptomycin [90, 101]
Competitive Inhibition Verapamil MATE- dinF and norM M. tuberculosis BedaquilineOfloxacin [102]
1-(1-napthylmethyl)-piperazine (NMP) RND- acrAB, acrEF E. coli LevofloxacinRifampinChloramphenicol [103]
2. Plant origin
Alkaloids Reserpine (Rawfolia serpentia) MFS- norA, tetK, Bmr MATE- mepA S. aureusBacillus subtilisStreptococcus pneumoniae NorfloxacinTetracyclineCiprofloxacin [104]
Piperine (Piper nigram) ABC transporters MFS- norA S. aureus, Mycobacterium tuberculosis CiprofloxacinRifampicin [105]
Conessine (Holarrheaa antidysenterica) RND- adeIJK, mexAB-oprM Acinetobacter baumannii Rifampicin Novobiocin [91]
Flavanoids Baicalein (Thymus vulgaris) MFS- tetK, norA Staphylococci TetracyclineCiprofloxacin [106, 107]
5′-methoxy-hydnocarpin (Berberis fremontii) MFS- norA S. aureus TetracyclineNorfloxacinBerberine [108]
Genistein (Isoflavone) MFS- norA S. aureus Berberine [109]
Epigallocatechin gallate MFS- tetK StaphylococciCamphylobacter TetracyclineErythromycinCiprofloxacin [110]
Polyphenols Curcumin (Curcuma longa) MFS- norA RND S. aureusP. aeruginosa NorfloxacinCiprofloxacinGentamicin [111, 112]
Coumarin (Mesua ferrea) MFS- norA S. aureus NorfloxacinCiprofloxacin [113]
Phenolic diterpenes Carnosic acid (Rosmarinus officinalis) ABC transporter msrA S. aureus Erythromycin [114]
Monoterpenoid Carnosol (Rosmarinus officinalis) ABC transporter msrA MFS- tetK S. aureus Tetracycline [114]
Geraniol (Helichrysum italicum) RND- acrAB-tolC Enterobacter aerogenes Chloramphenicol [115]
Catharanthine (Catharanthus roseus) RND- mexAB-oprM P. aeruginosa TetracyclineStreptomycin [116]
3. Synthetic origin
Quinolone derivatives Pyridoquinolones RND- acrAB-tolC Enterobacter aerogenes Norfloxacin [117]
Arylpiperidines and aryl piperazine derivatives Phenylpiperadines RND- acrAB-tolC E. coli Linezolid [118]
Pyridopyrimidine and pyranopyridine derivatives D2 and D13-9001MBX2319 RND- mexAB-oprMRND- acrAB-tolC P. aeruginosaE. coli FluoroquinolonesFluoroquinolones [119, 120][121]
Naphthyridine derivatives 1,8-naphthyridines sulfonamide MFS- norA S. aureus NorfloxacinEthidium bromide [97]
Boronic acid derivatives 6-(3-Phenylpropoxy) pyridine-3-boronic acid MFS- norA S. aureus CiprofloxacinEthidium bromide [122]
Indole derivatives 3-amino-6-carboxyl-indole3-nitro-6-amino-indole RND- acrAB-tolC E. coli ChloramphenicolTetracyclineErythromycinCiprofloxacin [123, 124]
4. Clinically approved drug
Hypoglycemic biguanide drug Metformin RND- acrAB-tolC MATE- mdtK K. pneumoniae Ampicillin-sulbactamMeropenemAmikacin [125]
Tyrosine kinase Inhibitor Nilotinib MFS- EmrD S. aureus Ciprofloxacin [86]
Ergot alkaloid-vasoconstrictor Dihydroergotamine MFS- norA S. aureus Ciprofloxacin [86]
5. Microbial origin
EA-371α and EA-371d (fermentation extract of Streptomyces spp. RND- mexAB-oprM P. aeruginosa Levofloxacin [126]

The chemical compound must follow specific criteria to make it an ideal EPI. The first and foremost rule is that the molecule must not be antibacterial. Secondly, it should be selective and target only bacterial EPs. Thirdly, it should be non-toxic with high therapeutic and safety indices and good ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) [127]. The toxicity of EPI can be lowered by co-administering them with membrane permeabilizing antimicrobial peptides (AMP) such as Polymyxin B nonapeptide (PMBN), which has five times lower toxicity than the parent compound polymyxin B [128]. The nephrotoxicity of PMBN was low when compared to polymyxin B (PMB) and polymyxin E (Colistin) in mice [129]. The cytotoxicity of polyamines towards eukaryotic cells are relatively low, and it would strongly enhance the antibacterial activity [85].

Computational approaches have led to the discovery of novel EPIs such as PAβN, novel pyranopyridine (D13-9001), and novel pyranopyridine (MBX2319) [130]. Molecular dynamics simulation (MDS), advanced three-dimensional structural resolution and molecular modelling can help identify possible inhibitors with pharmacophores that can detect a specific binding site on the EP [131]. Several studies have been made on the correlation of molecular interactions between EPIs and bacterial pumps via molecular docking [132].

In summary, EPs significantly contribute to drug resistance and survival of bacteria in the biofilm by extruding clinically relevant antibiotics. Therefore, the present investigation highlights that EPs could be an attractive target for antimicrobial drug development.

Fig. 1

Schematic representation of five superfamilies of EPs found in bacteria(ABC) ATP-Binding Cassette Superfamily [17]; (MFS) Major Facilitator Superfamily [18]; (MATE) Multidrug And Toxic Compound Extrusion Family [19]; (SMR) Small Multi-Drug Resistance Family [20]; (RND) Resistance-Nodulation-Division Superfamily [21].
Schematic representation of five superfamilies of EPs found in bacteria(ABC) ATP-Binding Cassette Superfamily [17]; (MFS) Major Facilitator Superfamily [18]; (MATE) Multidrug And Toxic Compound Extrusion Family [19]; (SMR) Small Multi-Drug Resistance Family [20]; (RND) Resistance-Nodulation-Division Superfamily [21].

List of Efflux Pump Inhibitors based on mechanism of action, origin, targets and substrates

Mechanism of action/Compounds EPIs Target EPs Bacteria Substrates References
1. Mechanism of Action
Energy Disruption CCCP-Carbonyl cyanide chlorophenyl hydrazone MFS- tetA, tetB H. pylori, Klebsiella spp. Tetracycline [98, 99]
Synthetic EPI- IITR08027 MATE- abeM E. coli, A. baumanii Fluoroquinolones [100]
PAβN RND- mexAB-oprM, mexCD-oprJ, mexEF-oprN P. aeruginosa LevofloxacinErythromycinStreptomycin [90, 101]
Competitive Inhibition Verapamil MATE- dinF and norM M. tuberculosis BedaquilineOfloxacin [102]
1-(1-napthylmethyl)-piperazine (NMP) RND- acrAB, acrEF E. coli LevofloxacinRifampinChloramphenicol [103]
2. Plant origin
Alkaloids Reserpine (Rawfolia serpentia) MFS- norA, tetK, Bmr MATE- mepA S. aureusBacillus subtilisStreptococcus pneumoniae NorfloxacinTetracyclineCiprofloxacin [104]
Piperine (Piper nigram) ABC transporters MFS- norA S. aureus, Mycobacterium tuberculosis CiprofloxacinRifampicin [105]
Conessine (Holarrheaa antidysenterica) RND- adeIJK, mexAB-oprM Acinetobacter baumannii Rifampicin Novobiocin [91]
Flavanoids Baicalein (Thymus vulgaris) MFS- tetK, norA Staphylococci TetracyclineCiprofloxacin [106, 107]
5′-methoxy-hydnocarpin (Berberis fremontii) MFS- norA S. aureus TetracyclineNorfloxacinBerberine [108]
Genistein (Isoflavone) MFS- norA S. aureus Berberine [109]
Epigallocatechin gallate MFS- tetK StaphylococciCamphylobacter TetracyclineErythromycinCiprofloxacin [110]
Polyphenols Curcumin (Curcuma longa) MFS- norA RND S. aureusP. aeruginosa NorfloxacinCiprofloxacinGentamicin [111, 112]
Coumarin (Mesua ferrea) MFS- norA S. aureus NorfloxacinCiprofloxacin [113]
Phenolic diterpenes Carnosic acid (Rosmarinus officinalis) ABC transporter msrA S. aureus Erythromycin [114]
Monoterpenoid Carnosol (Rosmarinus officinalis) ABC transporter msrA MFS- tetK S. aureus Tetracycline [114]
Geraniol (Helichrysum italicum) RND- acrAB-tolC Enterobacter aerogenes Chloramphenicol [115]
Catharanthine (Catharanthus roseus) RND- mexAB-oprM P. aeruginosa TetracyclineStreptomycin [116]
3. Synthetic origin
Quinolone derivatives Pyridoquinolones RND- acrAB-tolC Enterobacter aerogenes Norfloxacin [117]
Arylpiperidines and aryl piperazine derivatives Phenylpiperadines RND- acrAB-tolC E. coli Linezolid [118]
Pyridopyrimidine and pyranopyridine derivatives D2 and D13-9001MBX2319 RND- mexAB-oprMRND- acrAB-tolC P. aeruginosaE. coli FluoroquinolonesFluoroquinolones [119, 120][121]
Naphthyridine derivatives 1,8-naphthyridines sulfonamide MFS- norA S. aureus NorfloxacinEthidium bromide [97]
Boronic acid derivatives 6-(3-Phenylpropoxy) pyridine-3-boronic acid MFS- norA S. aureus CiprofloxacinEthidium bromide [122]
Indole derivatives 3-amino-6-carboxyl-indole3-nitro-6-amino-indole RND- acrAB-tolC E. coli ChloramphenicolTetracyclineErythromycinCiprofloxacin [123, 124]
4. Clinically approved drug
Hypoglycemic biguanide drug Metformin RND- acrAB-tolC MATE- mdtK K. pneumoniae Ampicillin-sulbactamMeropenemAmikacin [125]
Tyrosine kinase Inhibitor Nilotinib MFS- EmrD S. aureus Ciprofloxacin [86]
Ergot alkaloid-vasoconstrictor Dihydroergotamine MFS- norA S. aureus Ciprofloxacin [86]
5. Microbial origin
EA-371α and EA-371d (fermentation extract of Streptomyces spp. RND- mexAB-oprM P. aeruginosa Levofloxacin [126]

2019 antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, https://www.who.int/publications-detail-redirect/9789240000193 (2021) 2019 antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline https://www.who.int/publications-detail-redirect/9789240000193 2021 Search in Google Scholar

Kabra R., Chauhan N., Kumar A., Ingale P., Singh S.: Efflux pumps and antimicrobial resistance: Paradoxical components in systems genomics. Prog. Biophys. Mol. Biol. 141, 15–24 (2019) KabraR. ChauhanN. KumarA. IngaleP. SinghS. Efflux pumps and antimicrobial resistance: Paradoxical components in systems genomics Prog. Biophys. Mol. Biol. 141 15 24 2019 10.1016/j.pbiomolbio.2018.07.008 Search in Google Scholar

Reygaert W.C.: An overview of the antimicrobial resistance mechanisms of bacteria. AIMS. Microbiol. 4, 482–501 (2018) ReygaertW.C. An overview of the antimicrobial resistance mechanisms of bacteria AIMS. Microbiol. 4 482 501 2018 10.3934/microbiol.2018.3.482 Search in Google Scholar

Nikaido H.: Multiple antibiotic resistance and efflux. Curr. Opin. Microbiol. 1, 516–523 (1998) NikaidoH. Multiple antibiotic resistance and efflux Curr. Opin. Microbiol. 1 516 523 1998 10.1016/S1369-5274(98)80083-0 Search in Google Scholar

Langevin A.M., Dunlop M.J.: Stress introduction rate alters the benefit of AcrAB-TolCefflux pumps. J. Bacteriol. 200, e00525-17 (2017) LangevinA.M. DunlopM.J. Stress introduction rate alters the benefit of AcrAB-TolCefflux pumps J. Bacteriol. 200 e00525-17 2017 Search in Google Scholar

He X., Lu F., Yuan F., Jiang D., Zhao P., Zhu J., Cheng H., Cao J., Lu G.: Biofilm formation caused by clinical Acinetobacter baumannii isolates is associated with overexpression of the AdeFGH efflux pump. Antimicrob. Agents. Chemother. 59, 4817–4825 (2015) HeX. LuF. YuanF. JiangD. ZhaoP. ZhuJ. ChengH. CaoJ. LuG. Biofilm formation caused by clinical Acinetobacter baumannii isolates is associated with overexpression of the AdeFGH efflux pump Antimicrob. Agents. Chemother. 59 4817 4825 2015 10.1128/AAC.00877-15450522726033730 Search in Google Scholar

Favre-Bonté S., Köhler T., Van Delden C.: Biofilm formation by Pseudomonas aeruginosa: role of the C4-HSL cell-to-cell signal and inhibition by azithromycin. J. Antimicrob. Chemother. 52, 598–604 (2003) Favre-BontéS. KöhlerT. Van DeldenC. Biofilm formation by Pseudomonas aeruginosa: role of the C4-HSL cell-to-cell signal and inhibition by azithromycin J. Antimicrob. Chemother. 52 598 604 2003 10.1093/jac/dkg39712951348 Search in Google Scholar

Schembri M.A., Kjaergaard K., Klemm P.: Global gene expression in Escherichia coli biofilms. Mol. Microbiol. 48, 253–267 (2003) SchembriM.A. KjaergaardK. KlemmP. Global gene expression in Escherichia coli biofilms Mol. Microbiol. 48 253 267 2003 10.1046/j.1365-2958.2003.03432.x12657059 Search in Google Scholar

Diggle S.P., Winzer K., Lazdunski A., Williams P., Cámara M.: Advancing the quorum in Pseudomonas aeruginosa: MvaT and the regulation of N-acylhomoserine lactone production and virulence gene expression. J. Bacteriol. 184, 2576–2586 (2002) DiggleS.P. WinzerK. LazdunskiA. WilliamsP. CámaraM. Advancing the quorum in Pseudomonas aeruginosa: MvaT and the regulation of N-acylhomoserine lactone production and virulence gene expression J. Bacteriol. 184 2576 2586 2002 10.1128/JB.184.10.2576-2586.200213501211976285 Search in Google Scholar

Thanassi D.G., Cheng L.W., Nikaido H.: Active efflux of bile salts by Escherichia coli. J. Bacteriol. 179, 2512–2518 (1997) ThanassiD.G. ChengL.W. NikaidoH. Active efflux of bile salts by Escherichia coli J. Bacteriol. 179 2512 2518 1997 10.1128/jb.179.8.2512-2518.19971789979098046 Search in Google Scholar

Taylor D.L., Bina X.R., Bina J.E.: Vibrio cholerae VexH encodes a multiple drug efflux pump that contributes to the production of cholera toxin and the toxin co-regulated pilus. PloS One, 7, e38208 (2012) TaylorD.L. BinaX.R. BinaJ.E. Vibrio cholerae VexH encodes a multiple drug efflux pump that contributes to the production of cholera toxin and the toxin co-regulated pilus PloS One 7 e38208 2012 10.1371/journal.pone.0038208336422522666485 Search in Google Scholar

Schindler B.D., Kaatz G.W.: Multi-drug efflux pumps of Gram-positive bacteria. Drug. Resist. Updat. Rev. Comment. Antimicrob. Anticancer. Chemother. 27, 1–13 (2016) SchindlerB.D. KaatzG.W. Multi-drug efflux pumps of Gram-positive bacteria Drug. Resist. Updat. Rev. Comment. Antimicrob. Anticancer. Chemother. 27 1 13 2016 Search in Google Scholar

Li X-Z., Plésiat P., Nikaido H.: The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin. Microbiol. Rev. 28, 337–418 (2015) LiX-Z. PlésiatP. NikaidoH. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria Clin. Microbiol. Rev. 28 337 418 2015 10.1128/CMR.00117-14440295225788514 Search in Google Scholar

Handzlik J., Matys A., Kieć-Kononowicz K.: Recent advances in Multi-Drug Resistance (MDR) efflux pump inhibitors of Gram-positive bacteria S. aureus. Antibiotics, 2, 28–45 (2013) HandzlikJ. MatysA. Kieć-KononowiczK. Recent advances in Multi-Drug Resistance (MDR) efflux pump inhibitors of Gram-positive bacteria S. aureus Antibiotics 2 28 45 2013 10.3390/antibiotics2010028 Search in Google Scholar

Sharma A., Gupta V.K., Pathania R.: Efflux pump inhibitors for bacterial pathogens: From bench to bedside. Indian. J. Med. Res. 149, 129–145 (2019) SharmaA. GuptaV.K. PathaniaR. Efflux pump inhibitors for bacterial pathogens: From bench to bedside Indian. J. Med. Res. 149 129 145 2019 10.4103/ijmr.IJMR_2079_17 Search in Google Scholar

Auda I.G., Ali Salman I.M., Odah J.G.: Efflux pumps of Gram-negative bacteria in brief. Gene Reports, 100666 (2020) AudaI.G. Ali SalmanI.M. OdahJ.G. Efflux pumps of Gram-negative bacteria in brief Gene Reports 100666 2020 10.1016/j.genrep.2020.100666 Search in Google Scholar

Lubelski J., Konings W.N., Driessen A.J.M.: Distribution and physiology of ABC-type transporters contributing to multidrug resistance in bacteria. Microbiol. Mol. Biol. Rev. 71, 463–476 (2007) LubelskiJ. KoningsW.N. DriessenA.J.M. Distribution and physiology of ABC-type transporters contributing to multidrug resistance in bacteria Microbiol. Mol. Biol. Rev. 71 463 476 2007 10.1128/MMBR.00001-07 Search in Google Scholar

Pao SS., Paulsen I.T., Saier M.H. Jr.: Major facilitator superfamily. Microbiol Mol. Biol. Rev. 62, 1–34 (1998) PaoSS. PaulsenI.T. SaierM.H.Jr. Major facilitator superfamily Microbiol Mol. Biol. Rev. 62 1 34 1998 10.1128/MMBR.62.1.1-34.1998 Search in Google Scholar

Kuroda T., Tsuchiya T.: Multidrug efflux transporters in the MATE family. Biochim. Biophys. Acta. BBA – Proteins. Proteomics. 1794, 763–768 (2009) KurodaT. TsuchiyaT. Multidrug efflux transporters in the MATE family Biochim. Biophys. Acta. BBA – Proteins. Proteomics. 1794 763 768 2009 10.1016/j.bbapap.2008.11.012 Search in Google Scholar

Jack D.L., Yang N.M., Saier M.H Jr.: The drug/metabolite transporter superfamily: The DMT superfamily. Eur. J. Biochem. 268, 3620–3639 (2001) JackD.L. YangN.M. SaierM.HJr. The drug/metabolite transporter superfamily: The DMT superfamily Eur. J. Biochem. 268 3620 3639 2001 10.1046/j.1432-1327.2001.02265.x Search in Google Scholar

Nikaido H., Takatsuka Y.: Mechanisms of RND multidrug efflux pumps. Biochim. Biophys. Acta. BBA – Proteins. Proteomics. 1794, 769–781 (2009) NikaidoH. TakatsukaY. Mechanisms of RND multidrug efflux pumps Biochim. Biophys. Acta. BBA – Proteins. Proteomics. 1794 769 781 2009 10.1016/j.bbapap.2008.10.004 Search in Google Scholar

Mi W., Li Y., Yoon S.H., Ernst R.K., Walz T., Liao M.: Structural basis of MsbA-mediated lipopolysaccharide transport. Nature, 549, 233–237 (2017) MiW. LiY. YoonS.H. ErnstR.K. WalzT. LiaoM. Structural basis of MsbA-mediated lipopolysaccharide transport Nature 549 233 237 2017 10.1038/nature23649 Search in Google Scholar

Higgins C.F.: ABC transporters: physiology, structure and mechanism – an overview. Res. Microbiol. 152, 205–210 (2001) HigginsC.F. ABC transporters: physiology, structure and mechanism – an overview Res. Microbiol. 152 205 210 2001 10.1016/S0923-2508(01)01193-7 Search in Google Scholar

Xiong J., Mao D., Liu L.: Research progress on the role of ABC transporters in the drug resistance mechanism of intractable epilepsy. BioMed. Res. Int. 2015, 1–10 (2015) XiongJ. MaoD. LiuL. Research progress on the role of ABC transporters in the drug resistance mechanism of intractable epilepsy BioMed. Res. Int. 2015 1 10 2015 10.1155/2015/194541460048326491660 Search in Google Scholar

Wilkens S.: Structure and mechanism of ABC transporters. F1000Prime. Rep. 7, 14 (2015) WilkensS. Structure and mechanism of ABC transporters F1000Prime. Rep. 7 14 2015 10.12703/P7-14433884225750732 Search in Google Scholar

van Veen H.W., Venema K., Bolhuis H., Oussenko I., Kok J., Poolman B., Driessen A.J., Konings W.N.: Multidrug resistance mediated by a bacterial homolog of the human multidrug transporter MDR1. Proc. Natl. Acad. Sci. USA, 93, 10668–10672 (1996) van VeenH.W. VenemaK. BolhuisH. OussenkoI. KokJ. PoolmanB. DriessenA.J. KoningsW.N. Multidrug resistance mediated by a bacterial homolog of the human multidrug transporter MDR1 Proc. Natl. Acad. Sci. USA 93 10668 10672 1996 10.1073/pnas.93.20.10668382128855237 Search in Google Scholar

Dalmas O., Do Cao M-A., Lugo M.R., Sharom F.J., Di Pietro A., Jault M.A.: Time-resolved fluorescence resonance energy transfer shows that the bacterial multidrug ABC half-transporter BmrA functions as a homodimer. Biochemistry, 44, 4312–4321 (2005) DalmasO. Do CaoM-A. LugoM.R. SharomF.J. Di PietroA. JaultM.A. Time-resolved fluorescence resonance energy transfer shows that the bacterial multidrug ABC half-transporter BmrA functions as a homodimer Biochemistry 44 4312 4321 2005 10.1021/bi048280915766260 Search in Google Scholar

Fitzpatrick A.W.P., Du D. et al.: Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. Nat. Microbiol. 2, 17070 (2017) FitzpatrickA.W.P. DuD. Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump Nat. Microbiol. 2 17070 2017 10.1038/nmicrobiol.2017.70544782128504659 Search in Google Scholar

Choudhuri B.S., Bhakta S., Barik R., Basu J., Kundu M., Chakrabarti P.: Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis. Biochem. J. 367, 279–285 (2002) ChoudhuriB.S. BhaktaS. BarikR. BasuJ. KunduM. ChakrabartiP. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis Biochem. J. 367 279 285 2002 10.1042/bj20020615 Search in Google Scholar

Robertson G.T., Doyle T.B., Lynch A.S.: Use of an efflux-deficient Streptococcus pneumoniae strain panel to identify ABC-class multidrug transporters involved in intrinsic resistance to antimicrobial agents. Antimicrob. Agents. Chemother. 49, 4781–4783 (2005) RobertsonG.T. DoyleT.B. LynchA.S. Use of an efflux-deficient Streptococcus pneumoniae strain panel to identify ABC-class multidrug transporters involved in intrinsic resistance to antimicrobial agents Antimicrob. Agents. Chemother. 49 4781 4783 2005 10.1128/AAC.49.11.4781-4783.2005128015616251330 Search in Google Scholar

Hürlimann L.M., Corradi V., Hohl M., Bloemberg G.V., Tieleman D.P., Seeger M.A.: The heterodimeric ABC transporter EfrCD mediates multidrug efflux in Enterococcus faecalis. Antimicrob. Agents. Chemother. 60, 5400–5411 (2016) HürlimannL.M. CorradiV. HohlM. BloembergG.V. TielemanD.P. SeegerM.A. The heterodimeric ABC transporter EfrCD mediates multidrug efflux in Enterococcus faecalis Antimicrob. Agents. Chemother. 60 5400 5411 2016 10.1128/AAC.00661-16499786027381387 Search in Google Scholar

Al-Hamad A., Upton M., Burnie J.: Molecular cloning and characterization of SmrA, a novel ABC multi-drug efflux pump from Stenotrophomonas maltophilia. J. Antimicrob. Chemother. 64, 731–734 (2009) Al-HamadA. UptonM. BurnieJ. Molecular cloning and characterization of SmrA, a novel ABC multi-drug efflux pump from Stenotrophomonas maltophilia J. Antimicrob. Chemother. 64 731 734 2009 10.1093/jac/dkp27119643774 Search in Google Scholar

Matsuo T., Chen J., Minato Y., Ogawa W., Mizushima T., Kuroda T., Tsuchiya T.: SmdAB, a heterodimeric ABC-type multi-drug efflux pump, in Serratia marcescens. J. Bacteriol. 190, 648–654 (2008) MatsuoT. ChenJ. MinatoY. OgawaW. MizushimaT. KurodaT. TsuchiyaT. SmdAB, a heterodimeric ABC-type multi-drug efflux pump, in Serratia marcescens J. Bacteriol. 190 648 654 2008 10.1128/JB.01513-07222369118024518 Search in Google Scholar

Huda N., Lee E-W., Chen J., Morita Y., Kuroda T., Mizushima T., Tsuchiya T.: Molecular cloning and characterization of an ABC multidrug efflux pump, VcaM, in non-O1 Vibrio cholerae. Antimicrob. Agents. Chemother. 47, 413–2417 (2003) HudaN. LeeE-W. ChenJ. MoritaY. KurodaT. MizushimaT. TsuchiyaT. Molecular cloning and characterization of an ABC multidrug efflux pump, VcaM, in non-O1 Vibrio cholerae Antimicrob. Agents. Chemother. 47 413 2417 2003 10.1128/AAC.47.8.2413-2417.2003 Search in Google Scholar

Feng Z., Liu D., Liu Z., Liang Y., Wang Y., Liu Q., Liu Z., Zang Z., Cui Y.: Cloning and functional characterization of putative Escherichia coli ABC multidrug efflux transporter YddA. J. Microbiol. Biotechnol. 30, 982–995 (2020) FengZ. LiuD. LiuZ. LiangY. WangY. LiuQ. LiuZ. ZangZ. CuiY. Cloning and functional characterization of putative Escherichia coli ABC multidrug efflux transporter YddA J. Microbiol. Biotechnol. 30 982 995 2020 10.4014/jmb.2003.03003 Search in Google Scholar

Quistgaard E.M., Löw C., Guettou F., Nordlund P.: Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Nat. Rev. Mol. Cell. Biol. 17, 123–132 (2016) QuistgaardE.M. LöwC. GuettouF. NordlundP. Understanding transport by the major facilitator superfamily (MFS): structures pave the way Nat. Rev. Mol. Cell. Biol. 17 123 132 2016 10.1038/nrm.2015.25 Search in Google Scholar

Ren Q., Chen K., Paulsen I.T.: TransportDB: a comprehensive database resource for cytoplasmic membrane transport systems and outer membrane channels. Nucleic. Acids. Res. 35, D274–D279 (2007) RenQ. ChenK. PaulsenI.T. TransportDB: a comprehensive database resource for cytoplasmic membrane transport systems and outer membrane channels Nucleic. Acids. Res. 35 D274 D279 2007 10.1093/nar/gkl925 Search in Google Scholar

Henderson P.J.: The 12-transmembrane helix transporters. Curr. Opin. Cell. Biol. 5, 708–721 (1993) HendersonP.J. The 12-transmembrane helix transporters Curr. Opin. Cell. Biol. 5 708 721 1993 10.1016/0955-0674(93)90144-F Search in Google Scholar

Edgar R., Bibi E.: MdfA, an Escherichia coli multi-drug resistance protein with an extraordinarily broad spectrum of drug recognition. J. Bacteriol. 179, 2274 (1997) EdgarR. BibiE. MdfA, an Escherichia coli multi-drug resistance protein with an extraordinarily broad spectrum of drug recognition J. Bacteriol. 179 2274 1997 10.1128/jb.179.7.2274-2280.19971789649079913 Search in Google Scholar

Putman M., van Veen H.W., Degener J.E., Konings W.N.: The lactococcal secondary multidrug transporter LmrP confers resistance to lincosamides, macrolides, streptogramins and tetracyclines. Microbiology, 147, 2873–2880 (2001) PutmanM. van VeenH.W. DegenerJ.E. KoningsW.N. The lactococcal secondary multidrug transporter LmrP confers resistance to lincosamides, macrolides, streptogramins and tetracyclines Microbiology 147 2873 2880 2001 10.1099/00221287-147-10-287311577166 Search in Google Scholar

Fontaine F., Hequet A., Voisin-Chiret A.S., Bouillon A., Lesnard A., Cresteil T., Jolivalt C., Rault S.: First identification of boronic species as novel potential inhibitors of the Staphylococcus aureusNorA efflux pump. J. Med. Chem. 57, 2536–2548 (2014) FontaineF. HequetA. Voisin-ChiretA.S. BouillonA. LesnardA. CresteilT. JolivaltC. RaultS. First identification of boronic species as novel potential inhibitors of the Staphylococcus aureusNorA efflux pump J. Med. Chem. 57 2536 2548 2014 10.1021/jm401808n24499135 Search in Google Scholar

Bolhuis H., van Veen H.W., Poolman B., Driessen A.J., Konings W.N.: Mechanisms of multidrug transporters. FEMS. Microbiol. Rev. 21, 55–84 (1997) BolhuisH. van VeenH.W. PoolmanB. DriessenA.J. KoningsW.N. Mechanisms of multidrug transporters FEMS. Microbiol. Rev. 21 55 84 1997 10.1111/j.1574-6976.1997.tb00345.x9299702 Search in Google Scholar

Li X.Z., Nikaido H.: Efflux-mediated drug resistance in bacteria: an update. Drugs, 69, 1555–1623 (2009) LiX.Z. NikaidoH. Efflux-mediated drug resistance in bacteria: an update Drugs 69 1555 1623 2009 10.2165/11317030-000000000-00000284739719678712 Search in Google Scholar

Alav I., Kobylka J., Kuth M.S., Pos K.M., Picard M., Blair J.M.A., Bavro V.N.: Structure, assembly, and function of tripartite efflux and type 1 secretion systems in Gram-negative bacteria. Chem. Rev. 121, 5479–5596 (2021) AlavI. KobylkaJ. KuthM.S. PosK.M. PicardM. BlairJ.M.A. BavroV.N. Structure, assembly, and function of tripartite efflux and type 1 secretion systems in Gram-negative bacteria Chem. Rev. 121 5479 5596 2021 10.1021/acs.chemrev.1c00055827710233909410 Search in Google Scholar

Leung Y.M., Holdbrook D.A., Piggot T.J., Khalid S.: The NorM MATE transporter from N. gonorrhoeae: insights into drug and ion binding from atomistic molecular dynamics simulations. Biophys. J. 107, 460–468 (2014) LeungY.M. HoldbrookD.A. PiggotT.J. KhalidS. The NorM MATE transporter from N. gonorrhoeae: insights into drug and ion binding from atomistic molecular dynamics simulations Biophys. J. 107 460 468 2014 10.1016/j.bpj.2014.06.005410406025028887 Search in Google Scholar

Radchenko M., Symersky J., Nie R., Lu M.: Structural basis for the blockade of MATE multidrug efflux pumps. Nat. Commun. 6, 1–11 (2015) RadchenkoM. SymerskyJ. NieR. LuM. Structural basis for the blockade of MATE multidrug efflux pumps Nat. Commun. 6 1 11 2015 10.1038/ncomms8995486660026246409 Search in Google Scholar

Morita Y., Kodama K., Shiota S., Mine T., Kataoka A., Mizushima T., Tsuchiya T.: NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli. Antimicrob. Agents. Chemother. 42, 5 (1998) MoritaY. KodamaK. ShiotaS. MineT. KataokaA. MizushimaT. TsuchiyaT. NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli Antimicrob. Agents. Chemother. 42 5 1998 10.1128/AAC.42.7.17781056829661020 Search in Google Scholar

Kusakizako T., Miyauchi H., Ishitani R., Nureki O.: Structural biology of the multidrug and toxic compound extrusion superfamily transporters. Biochim. Biophys. Acta. BBA – Biomembr. 1862, 183154 (2020) KusakizakoT. MiyauchiH. IshitaniR. NurekiO. Structural biology of the multidrug and toxic compound extrusion superfamily transporters Biochim. Biophys. Acta. BBA – Biomembr. 1862 183154 2020 10.1016/j.bbamem.2019.18315431866287 Search in Google Scholar

Kaatz G.W., McAleese F., Seo S.M.: Multi-drug resistance in Staphylococcus aureus due to overexpression of a novel multi-drug and toxin extrusion (MATE) transport protein. Anti microb. Agents.Chemother. 49, 1857–1864 (2005) KaatzG.W. McAleeseF. SeoS.M. Multi-drug resistance in Staphylococcus aureus due to overexpression of a novel multi-drug and toxin extrusion (MATE) transport protein Anti microb. Agents.Chemother. 49 1857 1864 2005 10.1128/AAC.49.5.1857-1864.2005108764315855507 Search in Google Scholar

McAleese F., Petersen P., Ruzin A., Dunman PM., Murphy E., Projan SJ., Bradford PA.: A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline. Antimicrob. Agents. Chemother. 49, 1865–1871 (2005) McAleeseF. PetersenP. RuzinA. DunmanPM. MurphyE. ProjanSJ. BradfordPA. A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline Antimicrob. Agents. Chemother. 49 1865 1871 2005 10.1128/AAC.49.5.1865-1871.2005108764415855508 Search in Google Scholar

Tanihara Y., Masuda S., Sato T., Katsura T., Ogawa O., Inui K.: Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem. Pharmacol. 74, 359–371 (2007) TaniharaY. MasudaS. SatoT. KatsuraT. OgawaO. InuiK. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters Biochem. Pharmacol. 74 359 371 2007 10.1016/j.bcp.2007.04.01017509534 Search in Google Scholar

He G.X., Kuroda T., Mima T., Morita Y., Mizushima T., Tsuchiya T.: An H(+)–coupled multidrug efflux pump, PmpM, a member of the MATE family of transporters, from Pseudomonas aeruginosa. J. Bacteriol. 186, 262–265 (2004) HeG.X. KurodaT. MimaT. MoritaY. MizushimaT. TsuchiyaT. An H(+)–coupled multidrug efflux pump, PmpM, a member of the MATE family of transporters, from Pseudomonas aeruginosa J. Bacteriol. 186 262 265 2004 10.1128/JB.186.1.262-265.200430344914679249 Search in Google Scholar

Heir E., Sundheim G., Holck A.L.: The qacG gene on plasmid pST94 confers resistance to quaternary ammonium compounds in staphylococci isolated from the food industry. J. Appl. Microbiol. 86, 378–388 (1999) HeirE. SundheimG. HolckA.L. The qacG gene on plasmid pST94 confers resistance to quaternary ammonium compounds in staphylococci isolated from the food industry J. Appl. Microbiol. 86 378 388 1999 10.1046/j.1365-2672.1999.00672.x10196743 Search in Google Scholar

Bay D.C., Rommens K.L., Turner R.J.: Small multi-drug resistance proteins: A multi-drug transporter family that continues to grow. Biochim. Biophys. Acta. BBA – Biomembr. 1778, 1814–1838 (2008) BayD.C. RommensK.L. TurnerR.J. Small multi-drug resistance proteins: A multi-drug transporter family that continues to grow Biochim. Biophys. Acta. BBA – Biomembr. 1778 1814 1838 2008 10.1016/j.bbamem.2007.08.01517942072 Search in Google Scholar

Paulsen I.T., Skurray R.A., Tam R., Saier M.H. Jr., Turner R.J., Weiner J.H., Goldberg E.B., Grinius L.L.: The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic drugs. Mol. Microbiol. 19, 1167–1175 (1996) PaulsenI.T. SkurrayR.A. TamR. SaierM.H.Jr. TurnerR.J. WeinerJ.H. GoldbergE.B. GriniusL.L. The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic drugs Mol. Microbiol. 19 1167 1175 1996 10.1111/j.1365-2958.1996.tb02462.x8730859 Search in Google Scholar

Yerushalmi H., Lebendiker M., Schuldiner S.: EmrE, an Escherichia coli 12-kDa multidrug transporter, exchanges toxic cations and H+ and is soluble in organic solvents. J. Biol. Chem. 270, 6856–6863 (1995) YerushalmiH. LebendikerM. SchuldinerS. EmrE, an Escherichia coli 12-kDa multidrug transporter, exchanges toxic cations and H+ and is soluble in organic solvents J. Biol. Chem. 270 6856 6863 1995 10.1074/jbc.270.12.68567896833 Search in Google Scholar

Choudhary S., Sar P.: Real-time PCR based analysis of metal resistance genes in metal resistant Pseudomonas aeruginosa strain J007: Real-time PCR-based analysis of metal resistance genes. J. Basic. Microbiol. 56, 688–697 (2016) ChoudharyS. SarP. Real-time PCR based analysis of metal resistance genes in metal resistant Pseudomonas aeruginosa strain J007: Real-time PCR-based analysis of metal resistance genes J. Basic. Microbiol. 56 688 697 2016 10.1002/jobm.20150036426662317 Search in Google Scholar

Magnet S., Courvalin P., Lambert T.: Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM4454. Antimicrob. Agents. Chemother. 45, 3375–3380 (2001) MagnetS. CourvalinP. LambertT. Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM4454 Antimicrob. Agents. Chemother. 45 3375 3380 2001 10.1128/AAC.45.12.3375-3380.20019084011709311 Search in Google Scholar

Xu C., Bilya S.R., Xu W.: adeABC efflux gene in Acinetobacter baumannii. New. Microbes. New. Infect. 30, 100549 (2019) XuC. BilyaS.R. XuW. adeABC efflux gene in Acinetobacter baumannii New. Microbes. New. Infect. 30 100549 2019 10.1016/j.nmni.2019.100549653568931193498 Search in Google Scholar

Piddock L.J.V.: Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin. Microbiol. Rev. 19, 382–402 (2006) PiddockL.J.V. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria Clin. Microbiol. Rev. 19 382 402 2006 10.1128/CMR.19.2.382-402.2006147198916614254 Search in Google Scholar

Nakashima R., Sakurai K., Yamasaki S., Nishino K., Yamaguchi A.: Structures of the multi-drug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature, 480, 565–569 (2011) NakashimaR. SakuraiK. YamasakiS. NishinoK. YamaguchiA. Structures of the multi-drug exporter AcrB reveal a proximal multisite drug-binding pocket Nature 480 565 569 2011 10.1038/nature1064122121023 Search in Google Scholar

Du D., Wang Z., James N.R., Voss J.E., Klimont E., Ohene-Agyei T., Venter H., Chiu W., Luisi B.F.: Structure of the AcrAB-TolC multidrug efflux pump. Nature, 509, 512–515 (2014) DuD. WangZ. JamesN.R. VossJ.E. KlimontE. Ohene-AgyeiT. VenterH. ChiuW. LuisiB.F. Structure of the AcrAB-TolC multidrug efflux pump Nature 509 512 515 2014 10.1038/nature13205436190224747401 Search in Google Scholar

Li X.Z., Livermore D.M., Nikaido H.: Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob. Agents. Chemother. 38, 1732–1741 (1994) LiX.Z. LivermoreD.M. NikaidoH. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin Antimicrob. Agents. Chemother. 38 1732 1741 1994 10.1128/AAC.38.8.17322846307986003 Search in Google Scholar

Tsukazaki T.: Structure-based working model of SecDF, a proton-driven bacterial protein translocation factor. FEMS. Microbiol. Lett. 365, 112 (2018) TsukazakiT. Structure-based working model of SecDF, a proton-driven bacterial protein translocation factor FEMS. Microbiol. Lett. 365 112 2018 10.1093/femsle/fny112597478929718185 Search in Google Scholar

Alcalde-Rico M, Hernando-Amado S, Blanco P, Martínez J.L.: Multidrug efflux pumps at the crossroad between antibiotic resistance and bacterial virulence. Front. Microbiol. 7, 1483 (2016) Alcalde-RicoM Hernando-AmadoS BlancoP MartínezJ.L. Multidrug efflux pumps at the crossroad between antibiotic resistance and bacterial virulence Front. Microbiol. 7 1483 2016 10.3389/fmicb.2016.01483503025227708632 Search in Google Scholar

Soto S.M.: Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence, 4, 223–229 (2013) SotoS.M. Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm Virulence 4 223 229 2013 10.4161/viru.23724371198023380871 Search in Google Scholar

Liao J., Schurr M.J., Sauer K.: The MerR-like regulator BrlR confers biofilm tolerance by activating multidrug efflux pumps in Pseudomonas aeruginosa biofilms. J. Bacteriol. 195, 3352–3363 (2013) LiaoJ. SchurrM.J. SauerK. The MerR-like regulator BrlR confers biofilm tolerance by activating multidrug efflux pumps in Pseudomonas aeruginosa biofilms J. Bacteriol. 195 3352 3363 2013 10.1128/JB.00318-13371954023687276 Search in Google Scholar

Houry A., Gohar M., Deschamps J., Tischenko E., Aymerich S., Gruss A., Briandet R.: Bacterial swimmers that infiltrate and take over the biofilm matrix. Proc. Natl. Acad. Sci. 109, 13088–1309313 (2012) HouryA. GoharM. DeschampsJ. TischenkoE. AymerichS. GrussA. BriandetR. Bacterial swimmers that infiltrate and take over the biofilm matrix Proc. Natl. Acad. Sci. 109 13088 1309313 2012 10.1073/pnas.1200791109342016222773813 Search in Google Scholar

Lin Y.T., Huang Y.W., Chen S.J., Chang C.W., Yang T.C.: The SmeYZ efflux pump of Stenotrophomonas maltophilia contributes to drug resistance, virulence-related characteristics, and virulence in mice. Antimicrob. Agents. Chemother. 59, 4067–4073 (2015) LinY.T. HuangY.W. ChenS.J. ChangC.W. YangT.C. The SmeYZ efflux pump of Stenotrophomonas maltophilia contributes to drug resistance, virulence-related characteristics, and virulence in mice Antimicrob. Agents. Chemother. 59 4067 4073 2015 10.1128/AAC.00372-15446872125918140 Search in Google Scholar

Linares J.F., López J.A., Camafeita E., Albar J.P., Rojo F., Martínez J.L.: Overexpression of the multidrug efflux pumps MexCD-OprJ and MexEF-OprN is associated with a reduction of type III secretion in Pseudomonas aeruginosa. J. Bacteriol. 187, 1384–1391 (2005) LinaresJ.F. LópezJ.A. CamafeitaE. AlbarJ.P. RojoF. MartínezJ.L. Overexpression of the multidrug efflux pumps MexCD-OprJ and MexEF-OprN is associated with a reduction of type III secretion in Pseudomonas aeruginosa J. Bacteriol. 187 1384 1391 2005 10.1128/JB.187.4.1384-1391.200554560815687203 Search in Google Scholar

Tang M., Wei X., Wan X., Ding Z., Ding Y., Liu J.: The role and relationship with efflux pump of biofilm formation in Klebsiella pneumoniae. Microb. Pathog. 147, 104244 (2020) TangM. WeiX. WanX. DingZ. DingY. LiuJ. The role and relationship with efflux pump of biofilm formation in Klebsiella pneumoniae Microb. Pathog. 147 104244 2020 10.1016/j.micpath.2020.10424432437832 Search in Google Scholar

Sánchez P., Linares J.F., Ruiz-Díez B., Campanario E., Navas A., Baquero F., Martínez J.L.: Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants. J. Antimicrob. Chemother. 50, 657–664 (2002) SánchezP. LinaresJ.F. Ruiz-DíezB. CampanarioE. NavasA. BaqueroF. MartínezJ.L. Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants J. Antimicrob. Chemother. 50 657 664 2002 10.1093/jac/dkf18512407121 Search in Google Scholar

Alav I., Sutton J.M., Rahman K.M.: Role of bacterial efflux pumps in biofilm formation. J. Antimicrob. Chemother. 73, 2003–2020 (2018) AlavI. SuttonJ.M. RahmanK.M. Role of bacterial efflux pumps in biofilm formation J. Antimicrob. Chemother. 73 2003 2020 2018 10.1093/jac/dky04229506149 Search in Google Scholar

Akinpelu S., Ajayi A., Smith S.I., Adeleye A.I.: Efflux pump activity, biofilm formation and antibiotic resistance profile of Klebsiella spp. isolated from clinical samples at Lagos University Teaching Hospital. BMC Res. Notes. 13, 1–5 (2020) AkinpeluS. AjayiA. SmithS.I. AdeleyeA.I. Efflux pump activity, biofilm formation and antibiotic resistance profile of Klebsiella spp. isolated from clinical samples at Lagos University Teaching Hospital BMC Res. Notes. 13 1 5 2020 10.1186/s13104-020-05105-2724940732456668 Search in Google Scholar

Pasqua M., Grossi M., Zennaro A., Fanelli G., Micheli G., Barras F., Colonna B., Prosseda G.: The varied role of efflux pumps of the MFS family in the interplay of bacteria with animal and plant cells. Microorganisms, 7, e285 (2019) PasquaM. GrossiM. ZennaroA. FanelliG. MicheliG. BarrasF. ColonnaB. ProssedaG. The varied role of efflux pumps of the MFS family in the interplay of bacteria with animal and plant cells Microorganisms 7 e285 2019 10.3390/microorganisms7090285678098531443538 Search in Google Scholar

Scoffone V.C., Trespidi G., Barbieri G., Irudal S., Perrin E., Buroni S.: Role of RND efflux pumps in drug resistance of cystic fibrosis pathogens. Antibiot. Basel. Switz. 10, 863 (2021) ScoffoneV.C. TrespidiG. BarbieriG. IrudalS. PerrinE. BuroniS. Role of RND efflux pumps in drug resistance of cystic fibrosis pathogens Antibiot. Basel. Switz. 10 863 2021 10.3390/antibiotics10070863830070434356783 Search in Google Scholar

Ugwuanyi F.C., Ajayi A., Ojo D.A., Adeleye A.I., Smith S.I.: Evaluation of efflux pump activity and biofilm formation in multidrug resistant clinical isolates of Pseudomonas aeruginosa isolated from a Federal Medical Center in Nigeria. Ann. Clin. Microbiol. Antimicrob. 20, 11 (2021) UgwuanyiF.C. AjayiA. OjoD.A. AdeleyeA.I. SmithS.I. Evaluation of efflux pump activity and biofilm formation in multidrug resistant clinical isolates of Pseudomonas aeruginosa isolated from a Federal Medical Center in Nigeria Ann. Clin. Microbiol. Antimicrob. 20 11 2021 10.1186/s12941-021-00417-y785218933531042 Search in Google Scholar

Holling N., Jones B.V. et al.: Elucidating the genetic basis of crystalline biofilm formation in Proteus mirabilis. Infect. Immun. 82, 1616–1626 (2014) HollingN. JonesB.V. Elucidating the genetic basis of crystalline biofilm formation in Proteus mirabilis Infect. Immun. 82 1616 1626 2014 10.1128/IAI.01652-13399340324470471 Search in Google Scholar

Baugh S., Ekanayaka A.S., Piddock L.J., Webber M.A.: Loss of or inhibition of all multidrug resistance efflux pumps of Salmonella enterica serovar Typhimurium results in impaired ability to form a biofilm. J. Antimicrob. Chemother. 67, 2409–2417 (2012) BaughS. EkanayakaA.S. PiddockL.J. WebberM.A. Loss of or inhibition of all multidrug resistance efflux pumps of Salmonella enterica serovar Typhimurium results in impaired ability to form a biofilm J. Antimicrob. Chemother. 67 2409 2417 2012 10.1093/jac/dks22822733653 Search in Google Scholar

Krzyżek P., Grande R., Migdał P., Paluch E., Gościniak G.: Biofilm formation as a complex result of virulence and adaptive responses of Helicobacter pylori. Pathogens, 9, 1062 (2020) KrzyżekP. GrandeR. MigdałP. PaluchE. GościniakG. Biofilm formation as a complex result of virulence and adaptive responses of Helicobacter pylori Pathogens 9 1062 2020 10.3390/pathogens9121062776604433353223 Search in Google Scholar

Kvist M., Hancock V., Klemm P.: Inactivation of efflux pumps abolishes bacterial biofilm formation. Appl. Environ. Microbiol. 74, 7376–7382 (2008) KvistM. HancockV. KlemmP. Inactivation of efflux pumps abolishes bacterial biofilm formation Appl. Environ. Microbiol. 74 7376 7382 2008 10.1128/AEM.01310-08259291218836028 Search in Google Scholar

Magesh H., Kumar A., Alam A., Priyam., Sekar U., Sumantran V.N., Vaidyanathan R.: Identification of natural compounds which inhibit biofilm formation in clinical isolates of Klebsiella pneumoniae. Indian. J. Exp. Biol. 51, 764–772 (2013) MageshH. KumarA. AlamA. Priyam SekarU. SumantranV.N. VaidyanathanR. Identification of natural compounds which inhibit biofilm formation in clinical isolates of Klebsiella pneumoniae Indian. J. Exp. Biol. 51 764 772 2013 Search in Google Scholar

Rampioni G., Pillai C.R., Longo F., Bondì R., Baldelli V., Messina M., Imperi F., Visca P., Leoni L.: Effect of efflux pump inhibition on Pseudomonas aeruginosa transcriptome and virulence. Sci. Rep. 7, 11392 (2017) RampioniG. PillaiC.R. LongoF. BondìR. BaldelliV. MessinaM. ImperiF. ViscaP. LeoniL. Effect of efflux pump inhibition on Pseudomonas aeruginosa transcriptome and virulence Sci. Rep. 7 11392 2017 10.1038/s41598-017-11892-9559601328900249 Search in Google Scholar

Casalone E., Vignolini T., Braconi L., Gardini L., Capitanio M., Pavone F.S., Dei S., Teodori E.: 1-benzyl-1,4-diazepane reduces the efflux of resistance-nodulation-cell division pumps in Escherichia coli. Future. Microbiol. 15, 987–999 (2020) CasaloneE. VignoliniT. BraconiL. GardiniL. CapitanioM. PavoneF.S. DeiS. TeodoriE. 1-benzyl-1,4-diazepane reduces the efflux of resistance-nodulation-cell division pumps in Escherichia coli Future. Microbiol. 15 987 999 2020 10.2217/fmb-2019-029632840130 Search in Google Scholar

Fleeman R.M., Debevec G., Antonen K., Adams J.L., Santos R.G., Welmaker G.S., Houghten R.A., Giulianotti M.A., Shaw L.N.: Identification of a novel polyamine scaffold with potent efflux pump inhibition activity toward multi-drug resistant bacterial pathogens. Front. Microbiol. 9, 1301 (2018) FleemanR.M. DebevecG. AntonenK. AdamsJ.L. SantosR.G. WelmakerG.S. HoughtenR.A. GiulianottiM.A. ShawL.N. Identification of a novel polyamine scaffold with potent efflux pump inhibition activity toward multi-drug resistant bacterial pathogens Front. Microbiol. 9 1301 2018 10.3389/fmicb.2018.01301601054529963035 Search in Google Scholar

Zimmermann S., Klinger-Strobel M., Bohnert J.A., Wendler S., Rödel J., Pletz M.W., Löffler B., Tuchscherr L.: Clinically approved drugs inhibit the Staphylococcus aureus multidrug NorA efflux pump and reduce biofilm formation. Front. Microbiol. 10, 2762 (2019) ZimmermannS. Klinger-StrobelM. BohnertJ.A. WendlerS. RödelJ. PletzM.W. LöfflerB. TuchscherrL. Clinically approved drugs inhibit the Staphylococcus aureus multidrug NorA efflux pump and reduce biofilm formation Front. Microbiol. 10 2762 2019 10.3389/fmicb.2019.02762690166731849901 Search in Google Scholar

Mahey N., Tambat R., Verma D.K., Chandal N., Thakur K.G., Nandanwar H.: Antifungal azoles as tetracycline resistance modifiers in Staphylococcus aureus. Appl. Environ. Microbiol. 87, e00155–21 (2021) MaheyN. TambatR. VermaD.K. ChandalN. ThakurK.G. NandanwarH. Antifungal azoles as tetracycline resistance modifiers in Staphylococcus aureus Appl. Environ. Microbiol. 87 e00155 21 2021 10.1128/AEM.00155-21827681033990311 Search in Google Scholar

Nzakizwanayo J., Jones B.V. et al.: Fluoxetine and thioridazine inhibit efflux and attenuate crystalline biofilm formation by Proteus mirabilis. Sci. Rep. 7, 12222 (2017) NzakizwanayoJ. JonesB.V. Fluoxetine and thioridazine inhibit efflux and attenuate crystalline biofilm formation by Proteus mirabilis Sci. Rep. 7 12222 2017 10.1038/s41598-017-12445-w561033728939900 Search in Google Scholar

Chevalier J., Mahamoud A., Baitiche M., Adam E., Viveiros M., Smarandache A., Militaru A., Pascu M.L., Amaral L., Pagès J.M.: Quinazoline derivatives are efficient chemosensitizers of antibiotic activity in Enterobacter aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa resistant strains. Int. J. Antimicrob. Agents. 36, 164–168 (2010) ChevalierJ. MahamoudA. BaiticheM. AdamE. ViveirosM. SmarandacheA. MilitaruA. PascuM.L. AmaralL. PagèsJ.M. Quinazoline derivatives are efficient chemosensitizers of antibiotic activity in Enterobacter aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa resistant strains Int. J. Antimicrob. Agents. 36 164 168 2010 10.1016/j.ijantimicag.2010.03.02720494558 Search in Google Scholar

Lomovskaya O., Lee V.J. et al.: Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother. 45, 105–116 (2001) LomovskayaO. LeeV.J. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy Antimicrob Agents Chemother. 45 105 116 2001 10.1128/AAC.45.1.105-116.20019024711120952 Search in Google Scholar

Siriyong T., Srimanote P., Chusri S., Yingyongnarongkul B.E., Suaisom C., Tipmanee V., Voravuthikunchai S.P.: Conessine as a novel inhibitor of multidrug efflux pump systems in Pseudomonas aeruginosa. BMC. Complement. Altern. Med. 17, 405 (2017) SiriyongT. SrimanoteP. ChusriS. YingyongnarongkulB.E. SuaisomC. TipmaneeV. VoravuthikunchaiS.P. Conessine as a novel inhibitor of multidrug efflux pump systems in Pseudomonas aeruginosa BMC. Complement. Altern. Med. 17 405 2017 10.1186/s12906-017-1913-y555731028806947 Search in Google Scholar

Osei Sekyere J., Amoako D.G.: Carbonyl cyanide m-chlorophenylhydrazine (CCCP) reverses resistance to colistin, but not to carbapenems and tigecycline in multidrug-resistant Enterobacteriaceae. Front. Microbiol. 8, 228 (2017) Osei SekyereJ. AmoakoD.G. Carbonyl cyanide m-chlorophenylhydrazine (CCCP) reverses resistance to colistin, but not to carbapenems and tigecycline in multidrug-resistant Enterobacteriaceae Front. Microbiol. 8 228 2017 10.3389/fmicb.2017.00228530628228261184 Search in Google Scholar

Adabi M., Talebi-Taher M., Arbabi L., Afshar M., Fathizadeh S., Minaeian S., Moghadam-Maragheh N., Majidpour A.: Spread of efflux pump overexpressing-mediated fluoroquinolone resistance and multidrug resistance in Pseudomonas aeruginosa by using an efflux pump inhibitor. Infect Chemother. 47, 98–104 (2015) AdabiM. Talebi-TaherM. ArbabiL. AfsharM. FathizadehS. MinaeianS. Moghadam-MaraghehN. MajidpourA. Spread of efflux pump overexpressing-mediated fluoroquinolone resistance and multidrug resistance in Pseudomonas aeruginosa by using an efflux pump inhibitor Infect Chemother. 47 98 104 2015 10.3947/ic.2015.47.2.98449528126157587 Search in Google Scholar

Ikonomidis A., Tsakris A., Kanellopoulou M., Maniatis A.N., Pournaras S.: Effect of the proton motive force inhibitor carbonyl cyanide-m-chlorophenylhydrazone (CCCP) on Pseudomonas aeruginosa biofilm development. Lett. Appl. Cccp Microbiol. 47, 298–302 (2008) IkonomidisA. TsakrisA. KanellopoulouM. ManiatisA.N. PournarasS. Effect of the proton motive force inhibitor carbonyl cyanide-m-chlorophenylhydrazone (CCCP) on Pseudomonas aeruginosa biofilm development Lett. Appl. Cccp Microbiol. 47 298 302 2008 10.1111/j.1472-765X.2008.02430.x Search in Google Scholar

Durães F., Resende D.I.S.P., Palmeira A., Szemerédi N., Pinto M.M.M., Spengler G., Sousa E.: Xanthones active against multidrug resistance and virulence mechanisms of bacteria. Antibiotics, 10, 600 (2021) DurãesF. ResendeD.I.S.P. PalmeiraA. SzemerédiN. PintoM.M.M. SpenglerG. SousaE. Xanthones active against multidrug resistance and virulence mechanisms of bacteria Antibiotics 10 600 2021 10.3390/antibiotics10050600815868734069329 Search in Google Scholar

Oliveira-Tintino C.D.M., Silva T.G.D. et al.: The 1,8-naphthyridines sulfonamides are NorA efflux pump inhibitors. J. Glob. Antimicrob. Resist. 24, 233–240 (2021) Oliveira-TintinoC.D.M. SilvaT.G.D. The 1,8-naphthyridines sulfonamides are NorA efflux pump inhibitors J. Glob. Antimicrob. Resist. 24 233 240 2021 10.1016/j.jgar.2020.11.02733385589 Search in Google Scholar

Pule C.M., Sampson S.L., Warren R.M., Black P.A., van Helden P.D., Victor T.C., Louw G.E.: Efflux pump inhibitors: targeting myco-bacterial efflux systems to enhance TB therapy. J. Antimicrob. Chemother. 71, 17–26 (2016) PuleC.M. SampsonS.L. WarrenR.M. BlackP.A. van HeldenP.D. VictorT.C. LouwG.E. Efflux pump inhibitors: targeting myco-bacterial efflux systems to enhance TB therapy J. Antimicrob. Chemother. 71 17 26 2016 10.1093/jac/dkv31626472768 Search in Google Scholar

Fenosa A., Fusté E., Ruiz L., Veiga-Crespo P., Vinuesa T., Guallar V., Villa T.G., Viñas M.: Role of TolC in Klebsiella oxytoca resistance to antibiotics. J. Antimicrob. Chemother. 63, 668–674 (2009) FenosaA. FustéE. RuizL. Veiga-CrespoP. VinuesaT. GuallarV. VillaT.G. ViñasM. Role of TolC in Klebsiella oxytoca resistance to antibiotics J. Antimicrob. Chemother. 63 668 674 2009 10.1093/jac/dkp02719240073 Search in Google Scholar

Anoushiravani M., Falsafi T., Niknam V.: Proton motive force-dependent efflux of tetracycline in clinical isolates of Helicobacter pylori. J. Med. Microbiol. 58, 1309–1313 (2009) AnoushiravaniM. FalsafiT. NiknamV. Proton motive force-dependent efflux of tetracycline in clinical isolates of Helicobacter pylori J. Med. Microbiol. 58 1309 1313 2009 10.1099/jmm.0.010876-019574414 Search in Google Scholar

Bhattacharyya T., Sharma A., Akhter J., Pathania R.: The small molecule IITR08027 restores the antibacterial activity of fluoroquinolones against multidrug-resistant Acinetobacter baumannii by efflux inhibition. Int. J. Antimicrob. Agents. 50, 219–226 (2017) BhattacharyyaT. SharmaA. AkhterJ. PathaniaR. The small molecule IITR08027 restores the antibacterial activity of fluoroquinolones against multidrug-resistant Acinetobacter baumannii by efflux inhibition Int. J. Antimicrob. Agents. 50 219 226 2017 10.1016/j.ijantimicag.2017.03.00528533185 Search in Google Scholar

Renau T.E., Ohta T. et al., Nakayama K.: Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J. Med. Chem. 42, 4928–4931 (1999) RenauT.E. OhtaT. NakayamaK. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin J. Med. Chem. 42 4928 4931 1999 10.1021/jm990459810585202 Search in Google Scholar

Gupta S., Cohen K.A., Winglee K., Maiga M., Diarra B., Bishai W.R.: Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis. Antimicrob. Agents. Chemother. 58, 574–576 (2014) GuptaS. CohenK.A. WingleeK. MaigaM. DiarraB. BishaiW.R. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis Antimicrob. Agents. Chemother. 58 574 576 2014 10.1128/AAC.01462-13391072224126586 Search in Google Scholar

Bohnert J.A., Kern W.V.: Selected arylpiperazines are capable of reversing multi-drug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob. Agents. Chemother. 49, 849–852 (2005) BohnertJ.A. KernW.V. Selected arylpiperazines are capable of reversing multi-drug resistance in Escherichia coli overexpressing RND efflux pumps Antimicrob. Agents. Chemother. 49 849 852 2005 10.1128/AAC.49.2.849-852.200554722315673787 Search in Google Scholar

Stavri M., Piddock L.J.V., Gibbons S.: Bacterial efflux pump inhibitors from natural sources. J. Antimicrob. Chemother. 59, 1247–1260 (2007) StavriM. PiddockL.J.V. GibbonsS. Bacterial efflux pump inhibitors from natural sources J. Antimicrob. Chemother. 59 1247 1260 2007 10.1093/jac/dkl46017145734 Search in Google Scholar

Kumar A., Qazi G.N. et al.: Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus. J. Antimicrob. Chemother. 61, 1270–1276 (2008) KumarA. QaziG.N. Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus J. Antimicrob. Chemother. 61 1270 1276 2008 10.1093/jac/dkn08818334493 Search in Google Scholar

Chan B.C., Leung P.C. et al.: Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase. J. Ethnopharmacol. 137, 767–773 (2011) ChanB.C. LeungP.C. Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase J. Ethnopharmacol. 137 767 773 2011 10.1016/j.jep.2011.06.03921782012 Search in Google Scholar

Fujita M., Shiota S., Kuroda T., Hatano T., Yoshida T., Mizushima T., Tsuchiya T.: Remarkable synergies between baicalein and tetracycline, and baicalein and beta-lactams against methicillin-resistant Staphylococcus aureus. Microbiol. Immunol. 49, 391–396 (2005) FujitaM. ShiotaS. KurodaT. HatanoT. YoshidaT. MizushimaT. TsuchiyaT. Remarkable synergies between baicalein and tetracycline, and baicalein and beta-lactams against methicillin-resistant Staphylococcus aureus Microbiol. Immunol. 49 391 396 2005 10.1111/j.1348-0421.2005.tb03732.x15840965 Search in Google Scholar

Stermitz F.R., Lorenz P., Tawara J.N., Zenewicz L.A., Lewis K.: Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc. Natl. Acad. Sci. U S A. 97, 1433–1437 (2000) StermitzF.R. LorenzP. TawaraJ.N. ZenewiczL.A. LewisK. Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor Proc. Natl. Acad. Sci. U S A. 97 1433 1437 2000 10.1073/pnas.0305405972645110677479 Search in Google Scholar

AlMatar M., Albarri O., Makky E.A., Köksal F.: Efflux pump inhibitors: new updates. Pharmacol. Rep. PR. 73, 1–16 (2021) AlMatarM. AlbarriO. MakkyE.A. KöksalF. Efflux pump inhibitors: new updates Pharmacol. Rep. PR. 73 1 16 2021 10.1007/s43440-020-00160-932946075 Search in Google Scholar

SudanoRoccaro A., Blanco A.R., Giuliano F., Rusciano D., Enea V.: Epigallocatechin-gallate enhances the activity of tetracycline in staphylococci by inhibiting its efflux from bacterial cells. Antimicrob. Agents. Chemother. 48, 1968–1973 (2004) SudanoRoccaroA. BlancoA.R. GiulianoF. RuscianoD. EneaV. Epigallocatechin-gallate enhances the activity of tetracycline in staphylococci by inhibiting its efflux from bacterial cells Antimicrob. Agents. Chemother. 48 1968 1973 2004 10.1128/AAC.48.6.1968-1973.200441560115155186 Search in Google Scholar

Joshi P., Kumar A. et al.: Osthol and curcumin as inhibitors of human Pgp and multidrug efflux pumps of Staphylococcus aureus: reversing the resistance against frontline antibacterial drugs. Med. Chem. Comm. 5, 1540–1547 (2014) JoshiP. KumarA. Osthol and curcumin as inhibitors of human Pgp and multidrug efflux pumps of Staphylococcus aureus: reversing the resistance against frontline antibacterial drugs Med. Chem. Comm. 5 1540 1547 2014 10.1039/C4MD00196F Search in Google Scholar

Negi N., Prakash P., Gupta M.L., Mohapatra T.M.: Possible role of curcumin as an efflux pump inhibitor in multi drug resistant clinical isolates of Pseudomonas aeruginosa. J. Clin. Diagn. Res. JCDR. 8, DC04–DC07 (2014) NegiN. PrakashP. GuptaM.L. MohapatraT.M. Possible role of curcumin as an efflux pump inhibitor in multi drug resistant clinical isolates of Pseudomonas aeruginosa J. Clin. Diagn. Res. JCDR. 8 DC04 DC07 2014 10.7860/JCDR/2014/8329.4965425315825478340 Search in Google Scholar

Roy S., Kumari N., Pahwa S., Agrahari U., Bhutani K., Jachak S., Nandanwar H.: NorA efflux pump inhibitory activity of coumarins from Mesua ferrea. Fitoterapia, 90, 140–150 (2013) RoyS. KumariN. PahwaS. AgrahariU. BhutaniK. JachakS. NandanwarH. NorA efflux pump inhibitory activity of coumarins from Mesua ferrea Fitoterapia 90 140 150 2013 10.1016/j.fitote.2013.07.01523892000 Search in Google Scholar

Oluwatuyi M., Kaatz G.W., Gibbons S.: Antibacterial and resistance modifying activity of Rosmarinus officinalis. Phytochemistry, 65, 3249–3254 (2004) OluwatuyiM. KaatzG.W. GibbonsS. Antibacterial and resistance modifying activity of Rosmarinus officinalis Phytochemistry 65 3249 3254 2004 10.1016/j.phytochem.2004.10.00915561190 Search in Google Scholar

Lorenzi V., Muselli A., Bernardini A.F., Berti L., Pagès J.M., Amaral L., Bolla J.M.: Geraniol restores antibiotic activities against multidrug-resistant isolates from Gram-negative species. Antimicrob. Agents. Chemother. 53, 2209–2211 (2009) LorenziV. MuselliA. BernardiniA.F. BertiL. PagèsJ.M. AmaralL. BollaJ.M. Geraniol restores antibiotic activities against multidrug-resistant isolates from Gram-negative species Antimicrob. Agents. Chemother. 53 2209 2211 2009 10.1128/AAC.00919-08 Search in Google Scholar

Dwivedi G.R., Tyagi R., Sanchita., Tripathi S., Pati S., Srivastava S.K., Darokar M.P., Sharma A.: Antibiotics potentiating potential of catharanthine against superbug Pseudomonas aeruginosa. J. Biomol. Struct. Dyn. 36, 4270–284 (2018) DwivediG.R. TyagiR. Sanchita TripathiS. PatiS. SrivastavaS.K. DarokarM.P. SharmaA. Antibiotics potentiating potential of catharanthine against superbug Pseudomonas aeruginosa J. Biomol. Struct. Dyn. 36 4270 284 2018 10.1080/07391102.2017.1413424 Search in Google Scholar

Chevalier J., Atifi S., Eyraud A., Mahamoud A., Barbe J., Pagès J.M.: New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains. J. Med. Chem. 44, 4023–4026 (2001) ChevalierJ. AtifiS. EyraudA. MahamoudA. BarbeJ. PagèsJ.M. New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains J. Med. Chem. 44 4023 4026 2001 10.1021/jm010911z Search in Google Scholar

Kaatz G.W., Moudgal V.V., Seo S.M., Hansen J.B., Kristiansen J.E.: Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus. Int. J. Antimicrob. Agents. 22, 254–261 (2003) KaatzG.W. MoudgalV.V. SeoS.M. HansenJ.B. KristiansenJ.E. Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus Int. J. Antimicrob. Agents. 22 254 261 2003 10.1016/S0924-8579(03)00220-6 Search in Google Scholar

Opperman T.J., Nguyen S.T.: Recent advances toward a molecular mechanism of efflux pump inhibition. Front. Microbiol. 6, 421 (2015) OppermanT.J. NguyenS.T. Recent advances toward a molecular mechanism of efflux pump inhibition Front. Microbiol. 6 421 2015 10.3389/fmicb.2015.00421441985925999939 Search in Google Scholar

Mahmood H.Y., Jamshidi S., Sutton J.M., Rahman K.M.: Current advances in developing inhibitors of bacterial multi-drug efflux pumps. Curr. Med. Chem. 23, 1062–1081 (2016) MahmoodH.Y. JamshidiS. SuttonJ.M. RahmanK.M. Current advances in developing inhibitors of bacterial multi-drug efflux pumps Curr. Med. Chem. 23 1062 1081 2016 10.2174/0929867323666160304150522542565626947776 Search in Google Scholar

Vargiu A.V., Ruggerone P., Opperman T.J., Nguyen S.T., Nikaido H.: Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors. Antimicrob. Agents. Chemother. 58, 6224–6234 (2014) VargiuA.V. RuggeroneP. OppermanT.J. NguyenS.T. NikaidoH. Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors Antimicrob. Agents. Chemother. 58 6224 6234 2014 10.1128/AAC.03283-14418798725114133 Search in Google Scholar

Fontaine F., Héquet A., Voisin-Chiret A.S., Bouillon A., Lesnard A., Cresteil T., Jolivalt C., Rault S.: Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: study of 6-substituted pyridine-3-boronic acid derivatives. Eur. J. Med. Chem. 95, 185–198 (2015) FontaineF. HéquetA. Voisin-ChiretA.S. BouillonA. LesnardA. CresteilT. JolivaltC. RaultS. Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: study of 6-substituted pyridine-3-boronic acid derivatives Eur. J. Med. Chem. 95 185 198 2015 10.1016/j.ejmech.2015.02.05625817769 Search in Google Scholar

Zeng B., Wang H., Zou L., Zhang A., Yang X., Guan Z.: Evaluation and target validation of indole derivatives as inhibitors of the AcrAB-TolC efflux pump. Biosci. Biotechnol. Biochem. 74, 2237–2241 (2010) ZengB. WangH. ZouL. ZhangA. YangX. GuanZ. Evaluation and target validation of indole derivatives as inhibitors of the AcrAB-TolC efflux pump Biosci. Biotechnol. Biochem. 74 2237 2241 2010 10.1271/bbb.10043321071837 Search in Google Scholar

Rana T., Singh S., Kaur N., Pathania K., Gaur U.: A review on efflux pump inhibitors of medically important bacteria from plant sources. Int. J. Pharm. Sci. Rev. Res. 26, 101–111 (2014) RanaT. SinghS. KaurN. PathaniaK. GaurU. A review on efflux pump inhibitors of medically important bacteria from plant sources Int. J. Pharm. Sci. Rev. Res. 26 101 111 2014 Search in Google Scholar

Abbas H., Shaker G., Khattab R., Askoura M.: A new role of metformin as an efflux pump inhibitor in Klebsiella pneumonia. J. Microbiol. Biotechnol. Food Sci. 11, e4232–e4232 (2021) AbbasH. ShakerG. KhattabR. AskouraM. A new role of metformin as an efflux pump inhibitor in Klebsiella pneumonia J. Microbiol. Biotechnol. Food Sci. 11 e4232 e4232 2021 10.15414/jmbfs.4232 Search in Google Scholar

Lee M.D., Galazzo J.L., Staley A.L., Lee J.C., Warren M.S., Fuernkranz H., Chamberland S., Lomovskaya O., Miller G.H.: Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farm. Soc. Chim. Ital. 1989. 56, 81–85 (2001) LeeM.D. GalazzoJ.L. StaleyA.L. LeeJ.C. WarrenM.S. FuernkranzH. ChamberlandS. LomovskayaO. MillerG.H. Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance Farm. Soc. Chim. Ital. 1989. 56 81 85 2001 10.1016/S0014-827X(01)01002-3 Search in Google Scholar

Bhardwaj A.K., Mohanty P.: Bacterial efflux pumps involved in multi-drug resistance and their inhibitors: rejuvinating the antimicrobial chemotherapy. Recent. Patents. Anti-Infect. Drug. Disc. 7, 73–89 (2012) BhardwajA.K. MohantyP. Bacterial efflux pumps involved in multi-drug resistance and their inhibitors: rejuvinating the antimicrobial chemotherapy Recent. Patents. Anti-Infect. Drug. Disc. 7 73 89 2012 10.2174/15748911279982971022353004 Search in Google Scholar

Ferrer-Espada R., Shahrour H., Pitts B., Stewart P.S., Sánchez-Gómez S., Martínez-de-Tejada G.: A permeability-increasing drug synergizes with bacterial efflux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains. Sci. Rep. 9, 3452 (2019) Ferrer-EspadaR. ShahrourH. PittsB. StewartP.S. Sánchez-GómezS. Martínez-de-TejadaG. A permeability-increasing drug synergizes with bacterial efflux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains Sci. Rep. 9 3452 2019 10.1038/s41598-019-39659-4640111930837499 Search in Google Scholar

Keirstead N.D., Kern G. et al.: Early prediction of polymyxin-induced nephrotoxicity with next-generation urinary kidney injury biomarkers. Toxicol. Sci. 137, 278–291 (2014) KeirsteadN.D. KernG. Early prediction of polymyxin-induced nephrotoxicity with next-generation urinary kidney injury biomarkers Toxicol. Sci. 137 278 291 2014 10.1093/toxsci/kft24724189134 Search in Google Scholar

Rathi E., Kumar A., Kini S.G.: Computational approaches in efflux pump inhibitors: current status and prospects. Drug. Discov. Today. 25, 1883–1890 (2020) RathiE. KumarA. KiniS.G. Computational approaches in efflux pump inhibitors: current status and prospects Drug. Discov. Today. 25 1883 1890 2020 10.1016/j.drudis.2020.07.01132712312 Search in Google Scholar

Pagès J-M., Amaral L., Fanning S.: An original deal for new molecule: reversal of efflux pump activity, a rational strategy to combat Gram-negative resistant bacteria. Curr. Med. Chem. 18, 2969–2980 (2011) PagèsJ-M. AmaralL. FanningS. An original deal for new molecule: reversal of efflux pump activity, a rational strategy to combat Gram-negative resistant bacteria Curr. Med. Chem. 18 2969 2980 2011 10.2174/09298671179615046921651484 Search in Google Scholar

Mehla J., Zgurskaya H.I. et al.: Predictive rules of efflux inhibition and avoidance in Pseudomonas aeruginosa. mBio. 12, 02785–20 (2021) MehlaJ. ZgurskayaH.I. Predictive rules of efflux inhibition and avoidance in Pseudomonas aeruginosa mBio. 12 02785 20 2021 10.1128/mBio.02785-20784564333468691 Search in Google Scholar

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