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Inhibition of Drug Resistance of Staphylococcus aureus by Efflux Pump Inhibitor and Autolysis Inducer to Strengthen the Antibacterial Activity of β-lactam Drugs

WENJING LUAN
WENJING LUAN
, 
XIAOLEI LIU
XIAOLEI LIU
, 
XUEFEI WANG
XUEFEI WANG
, 
YANAN AN
YANAN AN
, 
YANG WANG
YANG WANG
, 
CHAO WANG
CHAO WANG
, 
KESHU SHEN
KESHU SHEN
, 
HONGYUE XU
HONGYUE XU
, 
SHULIN LI
SHULIN LI
, 
MINGYUAN LIU
MINGYUAN LIU
 and 
LU YU
LU YU
   | Dec 05, 2019
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Article Category: original-paper
Published Online: Dec 05, 2019
Page range: 477 - 491
Received: Jun 20, 2019
Accepted: Sep 21, 2019
DOI: https://doi.org/10.33073/pjm-2019-047
Keywords
© 2019 Wenjing Luan et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Fig. 1A i 1B.

Clinical observations of mammary tissue of mouse infected with Staphylococcus aureus ATCC 29213 or MRSA135 before and after treatment with the drugs.
Clinical observations of mammary tissue of mouse infected with Staphylococcus aureus ATCC 29213 or MRSA135 before and after treatment with the drugs.

Fig. 1C.

Clinical observations of mammary tissue of mouse infected with Staphylococcus aureus ATCC 29213 or MRSA135 before and after treatment with the drugs.
Clinical observations of mammary tissue of mouse infected with Staphylococcus aureus ATCC 29213 or MRSA135 before and after treatment with the drugs.

Fig. 2.

Histopathological observations for each group of mice (control, infected, and treated with the drugs).
Histopathological observations for each group of mice (control, infected, and treated with the drugs).

Fig. 3A i 3B

Fig. 3.

The culture of Staphylococcus aureus isolated from each group of mice (control, infected, treated with the drugs).MCZ – miconazole; TZ – thioridazine; CXN – cloxacillin; MCZ + TZ + CXN – the combination of miconazole, thioridazine, cloxacillin. There was no significant difference between the cloxacillin-treated and three-drugs-treated mice (P = 0.5649). The * on the horizontal line indicates a significant difference analysis between the CXN group and the three-drug group.* P < 0.05, ** p < 0.01, *** p < 0.0001.
The culture of Staphylococcus aureus isolated from each group of mice (control, infected, treated with the drugs).MCZ – miconazole; TZ – thioridazine; CXN – cloxacillin; MCZ + TZ + CXN – the combination of miconazole, thioridazine, cloxacillin. There was no significant difference between the cloxacillin-treated and three-drugs-treated mice (P = 0.5649). The * on the horizontal line indicates a significant difference analysis between the CXN group and the three-drug group.* P < 0.05, ** p < 0.01, *** p < 0.0001.

Fig. 4.

Drug effects on the cytokine level in mouse mastitis models.(A) Serum IFN-γ level in mice infected with ATCC 29213; (B) Serum IFN-γ level in mice infected with MRSA135; (C) Serum IL-6 level in mice infected with ATCC 29213; (D) Serum IL-6 level in mice infected with MRSA135; (E) Serum TNF-α level in mice infected with ATCC 29213; (F) Serum TNF-α level in mice infected with MRSA135; MCZ – miconazole; TZ – thioridazine; CXN – cloxacillin; MCZ + TZ + CXN – combination of miconazole, thioridazine, cloxacillin. The * on the horizontal line indicates a significant difference analysis between the CXN group and the three-drug group. * P < 0.05, **p < 0.01, ***p < 0.0001.
Drug effects on the cytokine level in mouse mastitis models.(A) Serum IFN-γ level in mice infected with ATCC 29213; (B) Serum IFN-γ level in mice infected with MRSA135; (C) Serum IL-6 level in mice infected with ATCC 29213; (D) Serum IL-6 level in mice infected with MRSA135; (E) Serum TNF-α level in mice infected with ATCC 29213; (F) Serum TNF-α level in mice infected with MRSA135; MCZ – miconazole; TZ – thioridazine; CXN – cloxacillin; MCZ + TZ + CXN – combination of miconazole, thioridazine, cloxacillin. The * on the horizontal line indicates a significant difference analysis between the CXN group and the three-drug group. * P < 0.05, **p < 0.01, ***p < 0.0001.

The activity of the combination of cloxacillin and miconazole against Staphylococcus aureus strains in vitro.

StrainsFICI
MRSA140.63
MRSA150.75
MRSA160.38
MRSA200.31
MRSA210.31
MRSA222.25
MRSA250.53
MRSA292.13
MRSA300.26
MRSA640.14
MRSA650.26
MRSA751.00
MRSA761.13
MRSA920.26
MRSA940.51
MRSA970.52
MRSA980.26
MRSA1250.50
MRSA1261.50
MRSA1341.50
MRSA1350.27
MRSA1421.01
MRSA1620.63
ATCC 292130.50
MSSA100.56
MSSA130.31
MSSA142.00
MSSA311.13
MSSA362.02
MSSA411.50
MSSA420.27
MSSA441.06
MSSA501.03
MSSA511.00
MSSA541.50
MSSA561.00
MSSA621.50
MSSA651.03
MSSA660.53
MSSA670.31
MSSA680.53
MSSA700.52
MSSA720.28
MSSA731.03
MSSA781.06
MSSA790.56
MSSA800.56

j.pjm-2019-047.tab.007

MRSA(methicillin-resistant S. aureus);
TZ(thioridazine);
MCZ(miconazole);
CXN(cloxacillin);
MIC(the minimum inhibitory concentration);
TNF-α(tumor necrosis factor-α);
IL-1β(interleukin 1β);
IL-6(interleukin 6);
IĸB(K-B inhibitor);
NF-KB(nuclear factor K-B);
CTCC(the China Type Culture Collection);
ATCC(American Type Culture Collection);
FIC(the fractional inhibitory concentration).

The activity of the combination of cloxacillin and thioridazine against Staphylococcus aureus strains in vitro.

StrainFICI
MRSA140.38
MRSA150.63
MRSA160.75
MRSA200.25
MRSA210.50
MRSA220.63
MRSA250.31
MRSA290.19
MRSA301.06
MRSA640.25
MRSA650.25
MRSA751.13
MRSA761.13
MRSA920.31
MRSA940.19
MRSA970.25
MRSA980.19
MRSA1250.27
MRSA1260.50
MRSA1340.16
MRSA1350.16
MRSA1420.63
MRSA1620.38
ATCC 292130.28
MSSA100.31
MSSA130.56
MSSA140.63
MSSA310.63
MSSA360.38
MSSA410.63
MSSA420.56
MSSA440.38
MSSA500.38
MSSA510.14
MSSA540.38
MSSA560.63
MSSA620.63
MSSA650.63
MSSA661.13
MSSA671.13
MSSA681.13
MSSA701.13
MSSA721.06
MSSA730.63
MSSA781.25
MSSA791.25
MSSA800.25

The MICs values of individual antimicrobial agents against Staphylococcus aureus isolates.

Antimicrobial agentsMIC (μg/ml)
Range50%90%
Cloxacillin4–51216512
Thioridazine16–643264
Miconazole1–848

Summary of thioridazine, miconazole and cloxacillin activity in combination (expressed as the MIC value) against Staphylococcus aureus strains.

Antimicrobial agentsMIC (μg/ml)
Range50%90%
CloxacillinThioridazine0.125–51216512
Miconazole0.25–5124512
Thioridazine + Miconazole0.000972–160.58

The activity of the combination of cloxacillin, thioridazine, and miconazole against MRSA strains in vitro.

StrainCXNTZMCZCXNTZMCZFICI
MICs (Single)MICs (Synergy)
MRSA14512322440.250.26
MRSA15512322240.250.25
MRSA16512164140.250.31
MRSA202563220.2540.250.25
MRSA211281640.540.250.32
MRSA22643240.2540.500.25
MRSA255121620.540.500.50
MRSA29256644440.500.20
MRSA305126440.540.500.19
MRSA64512328840.500.20
MRSA655123240.540.500.25
MRSA755123220.540.500.38
MRSA76512324840.500.27
MRSA925121640.007840.500.38
MRSA945123220.007840.500.38
MRSA972563220.015640.500.38
MRSA985123240.007840.500.25
MRSA1252561620.540.500.50
MRSA126256161140.500.75
MRSA1345123210.007840.500.63
MRSA1352563240.2540.500.25
MRSA142512321240.500.63
MRSA1625123241640.500.28
ATCC 2921341640.015640.500.38

The activity of the combination of cloxacillin, thioridazine, and miconazole against MSSA strains in vitro.

StrainCXNTZMCZCXNTZMCZFICI
MICs (Single)MICs (Synergy)
MSSA1016644440.250.38
MSSA138648840.251.09
MSSA148322840.251.25
MSSA3116322440.250.50
MSSA36163210.01562540.250.38
MSSA418321440.250.88
MSSA42166480.12540.250.10
MSSA44163210.540.250.41
MSSA50163210.12540.250.38
MSSA51163220.00197540.250.25
MSSA54161620.062540.250.38
MSSA56163220.0312540.250.25
MSSA62163220.000971540.250.25
MSSA65163220.12540.250.26
MSSA6616324440.250.44
MSSA6716324840.250.69
MSSA68163241640.251.19
MSSA70163240.01562540.250.19
MSSA72166480.540.250.13
MSSA73163220.062540.250.25
MSSA7881620.0312540.250.38
MSSA7981640.0312540.250.32
MSSA80163240.007812540.250.19
ATCC 2921341640.015640.500.38
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