The Rim pathway mediates antifungal tolerance in Candida albicans through newly identified Rim101 transcriptional targets, including Hsp90 and Ipt1
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ABSTRACT Invasive candidiasis (IC) is a major cause of morbidity and mortality despite antifungal treatment. Azoles and echinocandins are used as first-line therapies for IC. However, their efficacy is limited by yeast tolerance and the emergence of acquired resistance. Tolerance is a reversible stage created due to the yeast's capacity to counter antifungal drug exposure, leading to persistent growth. For Candida albicans , multiple stress signaling pathways have been shown to contribute to this adaptation. Among them, the pH-responsive Rim pathway, through its transcription factor Rim101p, was shown to mediate azole and echinocandin tolerance. The Rim pathway is fungus specific, is conserved among the members of the fungal kingdom, and plays a key role in pathogenesis and virulence. The present study aimed at confirming the role of Rim101p and investigating the implication of the other Rim proteins in antifungal tolerance in C. albicans , as well as the mechanisms underlying it. Time-kill curve experiments and colony formation tests showed that genetic inhibition of all the Rim factors enhances echinocandin and azole antifungal activity. Through RNA sequencing analysis of a rim101 −/− mutant, a strain constitutively overexpressing RIM101 , and control strains, we discovered novel Rim-dependent genes involved in tolerance, including HSP90 , encoding a major molecular chaperone, and IPT1 , involved in sphingolipid biosynthesis. Rim mutants were also hypersensitive to pharmacological inhibition of Hsp90. Taken together, these data suggest that Rim101 acts upstream of Hsp90 and that targeting the Rim pathway in combination with existing antifungal drugs may represent a promising antifungal strategy to indirectly but specifically target Hsp90 in yeasts.
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Transcriptomics and phenotypic analyses demonstrated that all Rim proteins, including RIM9 on ChrR, were important for FLC tolerance.
“Transcriptomics and phenotypic analyses demonstrated that all Rim proteins (including RIM9, on ChrR) were important for FLC tolerance (Garnaud et al. 2018).”
From Acquisition of cross-azole tolerance and aneuploidy in <i>Candida albicans</i> strains evolved to posaconazole (2022) · cites this paper as Garnaud et al. 2018
Hsp90 is involved in azole tolerance as part of the Rim pathway in C. albicans.
“Hsp90 is also involved in azole tolerance as part of the Rim pathway in C. albicans.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [169]
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- Authors
- Garnaud, C., García-Oliver, E., Wang, Y., Maubon, D., Bailly, S., Despinasse, Q., Champleboux, M., Govin, J., & Cornet, M.
- Affiliations
- Institut polytechnique de Grenoble (FR)
- Inserm (FR)
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2018-03
- Volume
- 62
- Issue
- 3
- Pages
- e01785-17
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC5826160
- OpenAlex
- W2783406767
- Cited by
- 41
- References
- 53
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 9 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 1 · 2018: 1
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-PDOC-0011)
- Fondation pour la Recherche Médicale (SPF20140129159)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Rim101, Candida albicans, antifungal tolerance, invasive candidiasis, HSP90, sphingolipid biosynthesis, azole resistance, echinocandin resistance, transcription factor target genes
- MeSH terms
- Antifungal Agents, Azoles, Candida albicans, Fungal Proteins, Signal Transduction, HSP90 Heat-Shock Proteins, Echinocandins
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