Dermatophyte Resistance to Antifungal Drugs: Mechanisms and Prospectus

Abstract

Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance. In addition, the ATP-binding cassette transporters in dermatophytes that are responsible for cellular efflux can act synergistically, allowing one to compensate for the absence of the other, revealing the complexity of drug tolerance phenomena. Moreover, mutations in genes coding for target enzymes could lead to substitutions in amino acids involved in the binding of antifungal agents, hindering their performance and leading to treatment failure. The relevance of each one of these mechanisms of resistance to fungal survival is hard to define, mainly because they can act simultaneously in the cell. However, an understanding of the molecular mechanisms involved in the resistance/tolerance processes, the identification of new antifungal targets, as well as the prospective of new antifungal compounds among natural or synthetic products, are expected to bring advances and new insights that facilitate the improvement or development of novel strategies for antifungal therapy.

Comparison of in vitro activities of 11 antifungal agents against Trichophyton verrucosum isolates associated with a variety hosts and geographical origin

“…An alarming trend of recalcitrant dermatophyte infections in Europe has been noted recently, which may be related to inadequate or discontinued treatment, difficulties in eliminating predisposing factors in hosts or infection sources, and frequent reinfections . In scientific literature, there are not many data available regarding drug resistance in dermatophytes, but it is suggested that the resistance is on the rise . In addition, only few reports revealed a correlation between in vitro resistance and therapeutic failure in dermatophyte infections .…”

“…However, this value was 0.72 μg/mL for the T. verrucosum isolates obtained from calves (Table ), and 0.79 and 0.196 for the isolates from Lithuania and Latvia, respectively (Table ). It can be suggested that the activity of this drug is higher in younger individuals or there are some regional determinants of resistance …”

“…Tinea and dermatophytosis are medical terms for superficial infection in animals and humans caused by these fungi . Although the infection is not life threatening, it may lead to local allergic reactions like pruritus, erythema and pustular lesions . Moreover, it can also lead to secondary bacterial infections…”

“…During the recent years, the increase in the occurrence of dermatophytosis along with the increase in the number of difficult‐to‐treat cases indicate that superficial fungal infections remain a public health challenge . Several causes of tolerance or resistance to antifungal agents have been mentioned, that is mutations in genes coding for target enzymes binding antifungal drugs, overexpression of genes involved in cellular detoxification, drug efflux and signalling pathways, and ATP‐binding cassette transporters . Therefore, it is reasonable to perform screening tests showing resistance to the currently available antifungal drugs and to discover new compounds with antifungal activity.…”

Discovery of a novel and selective fungicide that targets fungal cell wall to treat dermatomycoses: 1,3‐bis(3,4‐dichlorophenoxy)propan‐2‐aminium chloride

“…Approximately 20% of azole resistance in dermatophytes has been observed in some countries such as the United States and India . Primary resistance of T rubrum to terbinafine in cases of onychomycosis was described in 2003, and it is worth mentioning that in 2018 the resistance of dermatophytes continues being reported . For Candida spp., in patients of chronic mucocutaneous candidiasis, resistance to ketoconazole was first verified in 1980 and the problem of yeast resistance to azoles continues today, almost 40 years after that first report .…”