Chapter 16. Antifungal Resistance Mechanisms

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Antonio Ferreira-Pereira1, José Alexandre da Rocha Curvelo1, Anna Lea Silva Barreto1,2, Daniel Clemente de Moraesand Levy Tenório Sousa Domingos1
1Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
2Centro Universitário IBMR, Rio de Janeiro, RJ, Brazil

Part of the book: The Book of Fungal Pathogens

Abstract

The first antibiotic against fungi available for the treatment of fungal infections has been placed only in 1958, and it was a polyene, named Amphotericin B-deoxycholate. In the following years, new drugs emerged for the treatment of these infections, like griseofulvin, allylamines such as terbinafine, flucytosine, and the famous class of azoles, which includes the imidazoles such as miconazole and ketoconazole and the triazoles such as fluconazole and itraconazole. Recently, echinocandins, such as caspofungin and anidulafungin have been discovered and are currently available for clinical use. Unfortunately, fungal genus has already developed several mechanisms to circumvent drug action leading to clinical resistance for all these drugs cited above, even for the ones more recently described. Indeed, antifungal resistance is a huge therapeutic challenge and can be classified as microbiological (intrinsic or acquired) or clinical. In both cases, antifungal resistance expresses itself when a therapeutic concentration of the drug is not able to inhibit the growth of the pathogen, even when this specific concentration was supposed to do so, resulting in a low rate of therapeutic success and consequently an increase in the mortality rate. Furthermore, clinical resistance can be considered when the fungus is susceptible “in vitro,” but the same effect is not observed “in vivo” due to several factors such as the patient’s immune status. In fact, several mechanisms can lead to this situation, including the acquirement of mutations points that are able to modify enzymes or other antifungal target molecules, changes in the drug-target interaction, such as gene overexpression that increases antifungal target, as well as the inability of the drug to reach its target inside the cell, which may be caused by the permeability barriers or by an active drug pumping systems that can efflux antifungal drugs through transmembrane proteins such as ABC and MFS. Thus, the purpose of this chapter is to provide the reader with an analysis of the most important mechanisms that promote antibiotic resistance which can be very deleterious and sometimes fatal for the prognosis of fungal infections.

Keywords: antifungal mechanism, antifungal resistance, efflux pump, molds, yeasts


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