Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata

Abstract

Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures. prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable “genetic escape”. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata is highlighted.

Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall

“…On the other hand, combination of different classes of antifungal drugs to treat fungal infections may induce the emergence of mutidrug resistant pathogens and ultimately increase the therapeutic challenges in clinic. Echinocandins resistance in C. glabrata and C. abicans has been reported, while even more alarming, recent data show that FLC-resistant C. glabrata is also resistant to the echinocandins. , Thus, to avoid and combat the emergence of drug resistance, medicinal chemistry optimization of cell wall inhibitors should focus not only on the fungicidal activity and target selectivity but also on activating immune response by exposure of pathogen-associated molecular patterns like β-glucans and chitin, which is important for the innate immune cells to recognize the wall components and ultimately uptake and kill fungal invaders.…”

Histone Acetylation Regulator Gcn5 Mediates Drug Resistance and Virulence of Candida glabrata

“…Antifungal tolerance and resistance, impeding effective antifungal therapy and leading to unfavorable clinical outcomes, are two different but relevant phenotypes that fungal pathogens display in response to antifungal agents. Tolerance to fungicidal drugs is defined as the ability of fungal cells to survive at drug concentrations above the MIC ( 25 ), and tolerance is considered a key prerequisite for echinocandin resistance in C. glabrata ( 26 , 27 ). As for fungistatic drugs such as azoles, the concept can be adjusted, and it is reasonable to consider that Candida spp.…”

COVID-19-Associated Fungal Infections: An Urgent Need for Alternative Therapeutic Approach?

“…Microbial resistance is common in certain fungal species and involves both intrinsic resistance (strains are inherently less susceptible to a given antifungal agent), and secondary resistance (acquired resistance in an otherwise susceptible strain following drug exposure). The most notable species emerging worldwide and regarded as major concern for public health are triazole-resistant Aspergillus fumigatus ( Verweij et al, 2016 ; Romero et al, 2019 ; Yang et al, 2021 ), C. tropicalis, C. parapsilosis ( Pfaller et al, 2019 ), multidrug-resistant (MDR) Candida auris ( Chowdhary et al, 2018 ; Chaabane et al, 2019 ; Chow et al, 2020 ) and MDR C. glabrata showing increasing prevalence globally ( Haeley and Perlin, 2018 ). The narrow spectrum activity and cross-resistance due to similar mechanisms of action across drugs has triggered the search for safer alternatives with reduced toxicity, improved pharmacodynamics and pharmacokinetics, and increased specificity ( Parente-Rocha et al, 2017 ; Gintjee et al, 2020 ; Duncan et al, 2021 ).…”