Evolutionary dynamics in gut-colonizing Candida glabrata during caspofungin therapy: Emergence of clinically important mutations in sphingolipid biosynthesis.

Autor: Hassoun Y; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Aptekmann AA; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Keniya MV; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Gomez RY; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Alayo N; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Novi G; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Quinteros C; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Kaya F; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Zimmerman M; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America., Caceres DH; Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.; Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.; Studies in Translational Microbiology and Emerging Diseases (MICROS) Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia., Chow NA; Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America., Perlin DS; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America.; Hackensack Meridian School of Medicine, Nutley, New Jersey, United States of America.; Georgetown University Lombardi Comprehensive Cancer Center, Washington, D.C., United States of America., Shor E; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, United States of America.; Hackensack Meridian School of Medicine, Nutley, New Jersey, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2024 Sep 09; Vol. 20 (9), pp. e1012521. Date of Electronic Publication: 2024 Sep 09 (Print Publication: 2024).
DOI: 10.1371/journal.ppat.1012521
Abstrakt: Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting β-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like Candida glabrata, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (FKS1 and FKS2 in C. glabrata) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of C. glabrata colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this C. glabrata population during treatment and the emergence of both drug target (FKS2) and non-drug target mutations, the latter predominantly in the FEN1 gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The fen1 mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of YPC1 gene hypersensitized the wild type strain to caspofungin and was epistatic to fen1Δ. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in fen1Δ cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different fen1 mutations in clinical C. glabrata isolates, which phenocopied the fen1Δ mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with C. glabrata.
Competing Interests: DSP received an honorarium from N8 Biomedical, a mutual fund with more than $5,000 Merck stock, and an unlicensed patent for echinocandin resistance.
(Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
Databáze: MEDLINE
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