Molecular Mechanisms of Resistance to Antifungals in Candida albicans

Abstract

Invasive Candidiasis (IC) presents a global mortality rate greater than 40%, occupying the fourth place worldwide as the most frequent opportunistic nosocomial disease. Although the genus Candida consists of around 200 species, only 20 are reported as etiological agents of IC, being Candida albicans the most frequent causal agent. Even when there is a broad range of antifungals drugs for Candida infections, azoles, polyenes, and echinocandins are considered among the most effective treatment. However, there is some incidence for antifungal resistance among some Candida strains, limiting treatment options. Several molecular mechanisms with antifungal agents have been reported for C. albicans where insertions, deletions, and point mutations in genes codifying target proteins are frequently related to the antifungal drug resistance. Furthermore, gene overexpression is also frequently associated to antifungal resistance as well as an increase in the activity of proteins that reduce oxidative damage. This chapter summarizes the main molecular mechanisms to C. albicans antifungal drug resistance, besides offering an overview of new antifungal agents and new antifungal targets to combat fungal infections.

First report of amphotericin B resistant Candida haemulonii isolated from the ICU of a referral hospital in Indonesia

“…Like other Candida species, amphotericin B resistance is associated with amino acid changes in ERG2 and ERG11 ( 13 , 14 , 25 ). The characteristics of these amino acid changes are also thought to occur in C. haemulonii .…”

Sterol-targeted laboratory evolution allows the isolation of thermotolerant and respiratory-competent clones of the industrial yeast Saccharomyces cerevisiae

“…Then, we search for SNPs in genes involved in sterol production. The experimental evolution strategy adopted in this study was designed with the idea to promote mutations in ERG genes, which could result in both uconazole resistance [29] and increased thermotolerance [10,22]. Eighteen genes encoding for biosynthetic enzymes and well-known regulators [70] were inspected (Table S3).…”

“…FCNZ exposure inhibits 14 alpha-sterol demethylase, encoded by ERG11, which converts, through additional steps, lanosterol into ergosterol. This causes ergosterol depletion and accumulation of toxic 14α-methyl sterols [29]. Nevertheless, fungal FCNZ resistance is common, mainly as a result of mutations that alter activity and/or a nity of sterol pathway genes, among them ERG11, and ERG3 [29].…”

“…This causes ergosterol depletion and accumulation of toxic 14α-methyl sterols [29]. Nevertheless, fungal FCNZ resistance is common, mainly as a result of mutations that alter activity and/or a nity of sterol pathway genes, among them ERG11, and ERG3 [29]. In particular, the loss of Erg3 function leads to the exchange of 14α-methyl sterols for alternative, nontoxic intermediates [30].…”

Supramolecular Self-Associating Amphiphiles Inhibit Biofilm Formation by the Critical Pathogens, Pseudomonas aeruginosa and Candida albicans

“…albicans as one of the top four fungal pathogens in its critical priority group, demonstrating a significant unmet need for the development of novel therapeutic strategies to treat infections caused by this microorganism . One of the contributing factors to this is the ability of this yeast to form biofilms through the production of an extracellular polymeric substance, which consists of a complex structured network of glycoproteins, carbohydrates, lipids, and nucleic acids that directly contributes to pathogenic potential and fitness by providing antimicrobial protection. − …”