Antifungal Resistance Mechanisms in Dermatophytes

Abstract

Although fungi do not cause outbreaks or pandemics, the incidence of severe systemic fungal infections has increased significantly, mainly because of the explosive growth in the number of patients with compromised immune system. Thus, drug resistance in pathogenic fungi, including dermatophytes, is gaining importance. The molecular aspects involved in the resistance of dermatophytes to marketed antifungals and other cytotoxic drugs, such as modifications of target enzymes, over-expression of genes encoding ATP-binding cassette (ABC) transporters and stress-response-related proteins are reviewed. Emphasis is placed on the mechanisms used by dermatophytes to overcome the inhibitory action of terbinafine and survival in the host environment. The relevance of identifying new molecular targets, of expanding the understanding about the molecular mechanisms of resistance and of using this information to design new drugs or to modify those that have become ineffective is also discussed.

Antifungal Resistance Pattern among Dermatophytes in Western Rajasthan

“…This may also help in surveillance and epidemiological study of resistant strains. Table.1 Inhibition zone diameter criteria for susceptibility and Resistance of antifungal discs (Keyvan et al, 2009;Agarwal et al, 2015;Galuppi et al, 2010) Drug resistance mechanism among dermatophytes are acquired by stress adaptation against fluconazole, and terbinafine; modification of squalene epoxidase enzyme by mutation, overexpression of salicylate mono-oxygenase (drug degradation) against terbinafine; over expression of lanosterol-14a-demethylase and drug efflux against ketoconazole; drug efflux is the mechanism that is tool of resistance against all antifungal drugs by dermatophytes (Martinez et al, 2008). Biofilm formation has also been reported as a mechanism of drum resistance by T. Rubrum and T. mentagrophytes (Costa et al, 2014).…”

Dermatófitos: interação patógeno-hospedeiro e resistência a antifúngicos

“…In addition, commonly used antifungal drugs have a limited number of cell targets, such as ergosterol and the enzymes involved in its synthesis, nucleic acids and cell wall synthesis, and the formation of microtubules. 37 The treatment of dermatophytoses is often long and expensive, involving the use of drug CHART 1: Proteins identified in dermatophytes probably involved in virulence formulations of the allylamine and azole class, especially itraconazole and terbinafine. Combined treatments of topical and oral drugs and anti-inflammatories have been used in an attempt to increase cure rate.…”

“…The resistance of dermatophytes to inhibiting agents involves the participation of target-enzyme modifiers, overexpression of ATP binding cassette transporters and stress-related proteins. 37 In T. rubrum, two ATP binding cassette transporters, TruMDR1 e TruMDR2, were identified showing importance not only in the process of resistance to various antifungal drugs, but also in enzyme secretion and probably in the pathogenicity of this dermatophyte. [40][41][42] It has also been described that a mutation in the gene that codifies the enzyme squalene epoxidase (ErgA), target of terbinafine, made the fungi A. nidulans, Aspergillus fumigatus and T. rubrum highly resistant to this drug.…”

“…[40][41][42] It has also been described that a mutation in the gene that codifies the enzyme squalene epoxidase (ErgA), target of terbinafine, made the fungi A. nidulans, Aspergillus fumigatus and T. rubrum highly resistant to this drug. 37,43 Fungi respond to stimuli from the environment by the activation of several signal transduction pathways responsible for monitoring environmental alterations to allow the functioning of physiological mechanisms that adapt them to stress conditions, developing defense or cell tolerance responses. Antifungal drugs induce cell stress responses necessary to overcome their toxic effects, allowing the survival of the fungus.…”

“…Knowledge about fungal adaptive responses to adverse conditions promotes a better understanding about the biology of these microorganisms with the possibility of revealing essential metabolic pathways that allow their survival and, consequently, new cellular targets for the development of efficient drugs to control these infections. 37 Transcriptome analyses during exposure of T. rubrum to compounds with antifungal activity have led to the identification of genes involved in the adaptation and response to stress, and to the elucidation of the mechanism of action of drugs such as terbinafine, acriflavine, amphotericin B, and fluconazole, among others. 44,45 Studies about gene expression have also contributed to the evaluation of the effect of new antifungal agents on T. rubrum, such as the recently developed PHS11A and PH11B, which inhibit the fatty acid synthase enzyme.…”