DOI: 10.6084/m9.figshare.26509717
title: Antifungal resistance: why are we losing this battle?

description: The emergence of fungal pathogens and changes in the epidemiological landscape are prevalent issues in clinical mycology. Reports of resistance to antifungals have been reported. This review aims to evaluate molecular and nonmolecular mechanisms related to antifungal resistance. Mutations in the <i>ERG</i> genes and overexpression of the efflux pump (<i>MDR1, CDR1</i> and <i>CDR2</i> genes) were the most reported molecular mechanisms of resistance in clinical isolates, mainly related to Azoles. For echinocandins, a molecular mechanism described was mutation in the <i>FSK</i> genes. Furthermore, nonmolecular virulence factors contributed to therapeutic failure, such as biofilm formation and selective pressure due to previous exposure to antifungals. Thus, there are many public health challenges in treating fungal infections. The emergence of fungal pathogens and changes in scenery are a prevalent subject in clinical mycology. Species of non-<i>albicans Candida</i> spp. have been reported to cause invasive infection, surpassing the rates of <i>Candida albicans</i>, worldwide. Furthermore, there is also a constant report of resistance during the treatment of fungal infections. Presently, the clinical arsenal for systemic antifungals counts with different mechanisms of action and many classes. This review aims to group the molecular and nonmolecular mechanisms correlated with the resistance of nosocomial infections like <i>Candida</i> spp., <i>Aspergillus</i> spp. and <i>Cryptococcus</i> spp., to antifungals currently used in health services. The articles passed through three processes: identification, screening and eligibility. The identification was carried out in the following databases: EMBASE; MEDLINE; and COCHRANE. It included 74 articles. <i>ERG's</i> genes are responsible for regulating the synthesis of ergosterol, which is the major component of the fungal cell membrane and contributing with the fluidity and integrity of the membrane and the proper function of membrane-bound enzymes. The azole drugs block the synthesis by inhibiting the activity of the genes <i>ERG</i>, binding and inhibiting the lanosterol demethylase enzyme, causing damage to the cell membrane. In literature, we have a lot of findings with overexpression and mutation of different <i>ERG</i> genes, but the most frequent is <i>ERG11.</i> Mutations and super expression in the <i>ERG</i> genes, that are responsible for the ergosterol biosynthesis pathway, promote a resistance mechanism against azoles or Amphotericin b. The efflux pump is a mechanism where pathogens can export azole drugs from the inside of the cell. The expression is regulated by the genes <i>CDR2</i>, <i>CDR1</i> and <i>MDR1</i>, which coordinate the synthesis of ABC transporter proteins that act on the cell membrane exporting the azole substances. In cases of overexpression the synthesis of ABC transporters is superior causing bigger action of efflux pump, it contributes to a bigger exporting activite of azoles substances outside the cell conferring resistance. The fungal cell wall contains β-1,3-Glucan, which is synthesized by a membrane-integrated synthase encoded by <i>FKS</i> genes. For echinocandins, a molecular mechanism described was mutation in the <i>FSK</i> genes, these kinds of mutations have been shown to influence the sensibility of the GS enzyme complex to inhibition by the individual echinocandins. Furthermore, nonmolecular virulence factors contributed to therapeutic failure, such as biofilm formation, fungal melanins and selective pressure due to previous exposure to antifungals, and other factors that involved virulence factors and the host immunity system. Thus, there are many public health challenges in treating fungal infections. This study warns of the emergence of fungi resistant to the main antifungals of medical interest. Multiple molecular and nonmolecular mechanisms of antifungal resistance have been identified in several fungal pathogens, emphasizing the need for new strategies to contain fungal resistance. The use of tools for accurate laboratory diagnosis of fungal infections is necessary.