Multifactorial Role of Mitochondria in Echinocandin Tolerance Revealed by Transcriptome Analysis of Drug-Tolerant Cells

Abstract

Echinocandin drugs are a first-line therapy to treat invasive candidiasis, which is a major source of morbidity and mortality worldwide. The opportunistic fungal pathogen Candida glabrata is a prominent bloodstream fungal pathogen, and it is notable for rapidly developing echinocandin-resistant strains associated with clinical failure.

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

“…In comparison, transcriptomic changes in WT cells were more focused on upregulating cell wall integrity pathway genes as well as transmembrane transporter activity, suggesting that the cells were operating a concerted machinery to resist and repair cell wall damage induced by micafungin. This observation is also consistent with the most recently published study investigating transcriptomic alterations in C. glabrata cells surviving micafungin treatment ( 26 ).…”

“…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.…”

The importance of antimicrobial resistance in medical mycology

“…It appears that C. auris (Box 1) is highly resistant to azoles and also exhibits high levels of azole tolerance [45][46][47] . In C. glabrata, mitochondria play a role in the appearance of tolerance to echinocandins 48 .…”

“…C. auris is genetically diverged from more commonly observed Candida species, and the closest related species in the Candida haemulonii complex also display high rates of resistance. Studies of the genetic basis of resistance have identified high frequency mutations in drug targets (ERG11 and FKS1) as well as in the Tac1B and Mrr1 transcription factors 16 that control drug transporter expression that increase resistance to azoles and echinocandins, which vary in type and frequency between the four major genetic clades of C. auris 47,48 . By contrast, the mechanism of amphotericin resistance is largely unknown, aside from a report linking unusually high resistance levels to a loss of function mutation in the ERG6 protein involved in ergosterol biosynthesis 129 .…”

Drug Resistance and Novel Therapeutic Approaches in Invasive Candidiasis

“…Tolerance is another pathogen factor not detected by the MIC which affects fungal growth in vitro and may play a role in treatment response and resistance emergence. Tolerance is distinct from resistance and is defined as a subpopulation of cells within a susceptible isolate that grow and emerge slowly at supra-MIC fungistatic drug concentrations (azoles) ( Berman and Krysan, 2020 ) or survive at supra-MIC fungicidal concentrations (echinocandins) ( Healey and Perlin, 2018 ; Garcia-Rubio et al., 2021a ; Garcia-Rubio et al., 2021b ). Tolerant cells are more able to overcome drug pressures relative to the non-tolerant population through enhanced signalling in stress response pathways such as calcium signalling attenuated by the serine/threonine phosphatase calmodulin, HOG, Hsp90 and Tor ( Cowen and Steinbach, 2008 ; Rosenberg et al., 2018 ).…”