Unmasking of CgYor1-Dependent Azole Resistance Mediated by Target of Rapamycin (TOR) and Calcineurin Signaling in Candida glabrata

Kumari, Sonam; Kumar, Mohit; Esquivel, Brooke D.; Wasi, Mohd; Pandey, Ajay Kumar; Khandelwal, Nitesh; Mondal, Alok K.; White, Theodore C.; Prasad, Rajendra; Gaur, Naseem A.

doi:10.1128/mbio.03545-21

Cited by 3 publications

(3 citation statements)

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“…We investigated whether increased FLC diffusion/accumulation could explain the increased fluconazole susceptibility of ΔCgipt1 cells. We monitored FLC entry by measuring the intracellular accumulation of radiolabeled fluconazole ( 3 H-FLC) over time as explained earlier [ 45 ]. Briefly, ΔCgipt1 and WT cells were treated with 3 H-FLC with and cell samples were withdrawn at the indicated time interval and the intracellular FLC was measured.…”

Section: Resultsmentioning

confidence: 99%

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Inositol Phosphoryl Transferase, Ipt1, Is a Critical Determinant of Azole Resistance and Virulence Phenotypes in Candida glabrata

Shahi

Kumar

Khandelwal

et al. 2022

JoF

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In this study, we have specifically blocked a key step of sphingolipid (SL) biosynthesis in Candida glabrata by disruption of the orthologs of ScIpt1 and ScSkn1. Based on their close homology with S. cerevisiae counterparts, the proteins are predicted to catalyze the addition of a phosphorylinositol group onto mannosyl inositolphosphoryl ceramide (MIPC) to form mannosyl diinositolphosphoryl ceramide (M(IP)2C), which accounts for the majority of complex SL structures in S. cerevisiae membranes. High throughput lipidome analysis confirmed the accumulation of MIPC structures in ΔCgipt1 and ΔCgskn1 cells, albeit to lesser extent in the latter. Noticeably, ΔCgipt1 cells showed an increased susceptibility to azoles; however, ΔCgskn1 cells showed no significant changes in the drug susceptibility profiles. Interestingly, the azole susceptible phenotype of ΔCgipt1 cells seems to be independent of the ergosterol content. ΔCgipt1 cells displayed altered lipid homeostasis, increased membrane fluidity as well as high diffusion of radiolabeled fluconazole (3H-FLC), which could together influence the azole susceptibility of C. glabrata. Furthermore, in vivo experiments also confirmed compromised virulence of the ΔCgipt1 strain. Contrarily, specific functions of CgSkn1 remain unclear.

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Section: Resultsmentioning

confidence: 99%

“…The 3 H-FLC accumulation assay was performed as described previously [ 45 ]. Overnight-grown (16 h shaking cultures in YPD medium at 30 °C) samples were washed three times with YNB (yeast nitrogen base), starved of glucose for 3 h, and then treated with 3 H-FLC in YNB ± 2% glucose in technical duplicate.…”

Section: Methodsmentioning

confidence: 99%

Inositol Phosphoryl Transferase, Ipt1, Is a Critical Determinant of Azole Resistance and Virulence Phenotypes in Candida glabrata

Shahi

Kumar

Khandelwal

et al. 2022

JoF

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“…The target of rapamycin (TOR) signaling pathway is best studied as a therapeutic target in cancer, but given its central role in the regulation of cell cycle progression, stress responsivity, and protein synthesis, it may also represent a viable antifungal target (Fingar and Blenis, 2004). The TOR inhibitor sirolimus (rapamycin) was recently shown to disrupt the survival, morphogenesis, and stress responses of Candida and Aspergillus species while decreasing Candida azole tolerance (Kumari et al, 2022). Combining sirolimus with itraconazole (ITC), posaconazole (POS), and amphotericin B (AMB) also reportedly yields synergistic antifungal efficacy against Mucorales (Dannaoui et al, 2009).…”

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Analysis of the synergistic antifungal activity of everolimus and antifungal drugs against dematiaceous fungi

Jia²,

Tan³

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionChromoblastomycosis (CBM) is a form of chronic mycosis that affects the skin and mucous membranes and is caused by species of dematiaceous fungi including Exophiala spp., Phialophora spp., and Fonsecaea spp. The persistence of this disease and limitations associated with single-drug treatment have complicated efforts to adequately manage this condition.MethodsIn this study, a microdilution assay was used to explore the synergistic antifungal activity of everolimus (EVL) in combination with itraconazole (ITC), voriconazole (VRC), posaconazole (POS), and amphotericin B (AMB) against a range of clinical dematiaceous fungal isolates.ResultsThese analyses revealed that the EVL+POS and EVL+ITC exhibited superior in vitro synergistic efficacy, respectively inhibiting the growth of 64% (14/22) and 59% (13/22) of tested strains. In contrast, the growth of just 9% (2/22) of tested strains was inhibited by a combination of EVL+AMB, and no synergistic efficacy was observed for the combination of EVL+VRC.DiscussionOverall, these findings indicate that EVL holds promise as a novel drug that can be synergistically combined with extant antifungal drugs to improve their efficacy, thereby aiding in the treatment of CBM.

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Insights into the role of sphingolipids in antifungal drug resistance

Kalra,

Tanwar,

Bari

2024

Fungal Biology Reviews

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Unmasking of CgYor1-Dependent Azole Resistance Mediated by Target of Rapamycin (TOR) and Calcineurin Signaling in Candida glabrata

Abstract: The increasing incidence of Candida glabrata infections in the last 40 years is a serious concern worldwide. These infections are usually associated with intrinsic azole resistance and increasing echinocandin resistance.

Cited by 3 publications

References 96 publications

Inositol Phosphoryl Transferase, Ipt1, Is a Critical Determinant of Azole Resistance and Virulence Phenotypes in Candida glabrata

Inositol Phosphoryl Transferase, Ipt1, Is a Critical Determinant of Azole Resistance and Virulence Phenotypes in Candida glabrata

Analysis of the synergistic antifungal activity of everolimus and antifungal drugs against dematiaceous fungi

Insights into the role of sphingolipids in antifungal drug resistance

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