Mechanisms Of Dermatophyte Resistance To Antifungal Substances

Dermatophytes are pathogenic fungi with high affinity for keratinised structures present in nails, skin, and hair causing superficial infections known as skin mycoses or dermatomycoses. The disease is characterised by variable prognosis. Its clinical picture is largely dependent on the immune status of the host and can range from local skin or subcutaneous infections to invasive, disseminated, and life-threatening infections. In the first decades of the 20th century, the first concerns were raised about the growing prevalence of fungal infections in humans, which was ascribed to various environmental factors and anthropopressure. Consequently, the first therapeutic attempts were made to treat these infections. At present, at least several different groups of antifungal drugs are available for medical treatment. Nevertheless, the overlapping mechanisms of action of these substances and discontinuation of therapy by patients may contribute to the emergence of resistance of strains, including multi-drug resistance. The aim of this study is to review the literature focused on the mechanisms of resistance developed by dermatophytes to antifungal substances. Through evolution, these fungi have developed complex cellular response systems comprising elements of the environment-cell signalling system, responses to stressors, and tolerance to harmful chemical substances. Such stimuli as exposure of dermatophytes to an antifungal drug, damage to their cell wall, and disturbances in the osmolarity of the environment with generation of reactive oxygen species can be activators of signalling pathways targeted at mitigation of the effects of sudden cellular stress. A majority of molecular mechanisms underlying the response to these stressors also constitute a mechanism of tolerance and resistance to antifungal substances. In the future, elucidation of these mechanisms may lead to development of new chemotherapeutics that will become a key strategy in the treatment of dermatophyte strains exhibiting resistance to currently available antifungal drugs.

1. Introduction. 2. Current antifungal drugs. 3. Exposure of the pathogen to drugs, stress response, and adaptation. 4. Mechanisms of drug efflux from the cell. 5. Mechanisms of drug detoxification. 6. Transcriptional modulation of signalling pathway genes. 7. Role of heat shock proteins in drug resistance. 8. Mutations in target enzyme genes inducing drug resistance. 9. Structural elements of the cell contributing to drug resistance. 10. Summary