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 5 publications

(5 citation statements)

References 96 publications

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“…The MKC1 gene encodes mitogen-activated protein (MAP) kinase, a key component of the PKC pathway [ 24 ]. The LRG1 gene encodes Lrg1p, which inhibits the GTPase, Rho1, an activator of the PKC1 pathway [ 25 ]. In vivo drug resistance may also involve host environmental stressors [ 16–22 ].…”

Section: Resultsmentioning

confidence: 99%

Evolutionary accumulation of FKS 1 mutations from clinical echinocandin-resistant Candida auris

Tian,

Wu,

et al. 2024

Emerging Microbes & Infections

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Introduction: Drug resistance to echinocandins, first-line drugs used to treat Candida auris infection, is rapidly emerging. However, the accumulation of mutations in genes other than FKS 1 (before an isolate develops to resistance via FKS 1 mutations), remains poorly understood. Methods: Four clinical cases and 29 isolates associated with the incremental process of echinocandin resistance were collected and analyzed using antifungal drug susceptibility testing and genome sequencing to assess the evolution of echinocandin resistance. Findings: Six echinocandin minimum inhibitory concentration (MIC)-elevated C. auris strains and seven resistant strains were isolated from the urinary system of patients receiving echinocandin treatment. Meanwhile, phylogenetic analyses illustrated that the echinocandin-resistant strains were closely related to other strains in the same patient. Genomic data revealed that the echinocandin-resistant strains had FKS 1 mutations. Furthermore, three categories (ECN-S/E/R) of non-synonymous mutant SNP genes (such as RBR 3, IFF 6, MKC 1, MPH 1, RAD 2, and MYO 1) in C. auris appeared to be associated with the three-stage-evolutionary model of echinocandin resistance in C. glabrata : cell wall stress, drug adaptation, and genetic escape ( FKS mutation). Interpretation: Echinocandin-resistant C. auris undergoes spatial and temporal phase changes closely related to echinocandin exposure, particularly in the urinary system. These findings suggest that FKS1 mutations mediate an evolutionary accumulation of echinocandin resistance followed by modulation of chromosome remodelling and DNA repair processes that ultimately lead to FKS 1 hot spot mutations and the development of drug resistance. This study provides an in-depth exploration of the molecular pathways involved in the evolution of Candida auris echinocandin resistance.

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Section: Resultsmentioning

confidence: 99%

Evolutionary accumulation of FKS 1 mutations from clinical echinocandin-resistant Candida auris

Tian,

Wu,

et al. 2024

Emerging Microbes & Infections

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“…Células fúngicas com deleção do gene transportador Cg yor1 Δ demonstraram suscetibilidade aos azóis, em condições de escassez de nitrogênio, independente do transportador CgCdr1. Essas células também mostraram maior suscetibilidade a mTOR e inibidores da calcineurina (KUMARI et al, 2022).…”

Section: Resultsunclassified

Rapamicina No Tratamento Da Candidíase Sistêmica: Uma Revisão

Abreu,

SILVA

2023

Anais Do III Congresso Brasileiro De Imunologia on-Line

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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%

“…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

Self Cite

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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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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 5 publications

References 96 publications

Evolutionary accumulation of FKS 1 mutations from clinical echinocandin-resistant Candida auris

Evolutionary accumulation of FKS 1 mutations from clinical echinocandin-resistant Candida auris

Rapamicina No Tratamento Da Candidíase Sistêmica: Uma Revisão

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

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