Resistance to echinocandin-class antifungal drugs

Abstract

Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandins drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking β-1,3-D-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by one thousand-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom.

De Novo Acquisition of Resistance to SCY-078 in Candida glabrata Involves FKS Mutations That both Overlap and Are Distinct from Those Conferring Echinocandin Resistance

“…The isolated enzymes harboring mutations in or outside the echinocandin-resistant HS regions were more sensitive to MCF, with an IC 50 between 3-to 43-fold lower than those for SCY-078. Of the 15 SCY-078-resistant isolates generated from the screen showing FKS mutations, 13 of them contained a mutation in FKS2, correlating with previous findings that glucan synthase expression may be predominantly derived from FKS2 in C. glabrata (11). The absence of mutations found at prominent echinocandin resistance hot spot loci Ser663 (FKS2) and Ser629 (FKS1) is consistent with in vitro studies showing that SCY-078 is active against echinocandin-resistant strains with mutations at these positions (4,5).…”

“…Reduced echinocandin susceptibility leading to therapeutic failure has been linked to mutations in two highly conserved hot spot regions (HS1 and HS2) in the catalytic FKS subunit of ␤-(1,3)-D-glucan synthase (10,11). Since SCY-078 also targets ␤-(1,3)-Dglucan synthase, we determined the spectrum of possible mutations in the SR C. glabrata isolates by sequencing both FKS1 and FKS2 genes.…”

Activity of phenolic compounds from plant origin against Candida species

“…Despite a higher level of efficiency associated to this class of antifungal drugs, exerting rapid fungicidal effects against Candida species, including azole-resistance species (Kontoyiannis and Lewis, 2002), in the last years, it has been observed an increasing level of resistance, namely for C. albicans, C. glabrata, C. krusei and C. parapsilosis (Kanafani and Perfect, 2008;Perlin, 2009). The involved resistance mechanisms were not completely elucidated and other are still unknown; however, drug tolerance conferred by adaptive cellular physiology to the environmental stress, as well as genetic mutations and amino acids substitutions are the main supposed contributors associated with Candida species echinocandin-resistant (Perlin, 2009 (Kanafani and Perfect, 2008;Perlin, 2014Perlin, , 2009Sanglard, 2002). So, considering all the advances on antifungal drugs research, it is necessary to take into account the safety, tolerability, efficacy, toxicity and, even side effects of these substances/chemical molecules.…”

Target validation and ligand development for a pathogenic fungal profilin, using a knock‐down strain of pathogenic yeast Candida glabrata and structure‐based ligand design

“…To make matters worse, the number of effective antifungal drugs is limited, and resistant strains to frequently-used drugs, including echinocandin, have been emerging in clinical settings (Perlin, 2007). In this background, offering novel drug targets and inhibitors or ligands will help in antifungal drug development (Jiang et al, 2008;Xu et al, 2009).…”