Resistance to echinocandin-class antifungal drugs.

Perlin, David S.

doi:10.1016/j.drup.2007.04.002

Cited by 512Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Resistance to echinocandin-class antifungal drugs.

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Perlin, David S.·2007·Drug Resistance Updates

DOI 10.1016/j.drup.2007.04.002PMC PMC2696280

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Abstract

Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandin drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking beta-1,3-d-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by 1000-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom.

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The only echinocandin resistance mechanism described is mutation in the drug target Fks, particularly in highly conserved hot spot regions.
“Thus far, the only echinocandin resistance mechanism described is mutation in the drug target, Fks, particularly in highly conserved hot spots regions [33], [36]–[39].”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [33]
Section 12 says Fks1 mutations are the only mechanism firmly associated with clinical echinocandin resistance, and sections 7–8 locate those mutations in conserved hot spots. But section 11 describes echinocandin-resistant fungi whose resistance indicates an alternative mechanism independent of Fks1. The claim's unqualified assertion that Fks mutation is the only described resistance mechanism is therefore contrary to the source. (LLM, conf=0.87)
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The most common mechanism of echinocandin resistance is mutation of the drug target.
“The most common mechanism of echinocandin resistance is mutation of the drug target [11].”
From Hsp90 Governs Echinocandin Resistance in the Pathogenic Yeast Candida albicans via Calcineurin (2009) · cites this paper as [11]
The echinocandins are generally fungicidal against yeast species such as C. albicans.
“The echinocandins are generally fungicidal against yeast species such as C. albicans [11].”
From Hsp90 Governs Echinocandin Resistance in the Pathogenic Yeast Candida albicans via Calcineurin (2009) · cites this paper as [11]
An extensive list of mutations in hot-spot regions of the genes encoding the echinocandin target has been characterised and associated with species- and drug-specific loss of susceptibility.
“An extensive list of mutations in hot-spot regions of the genes encoding the target has been characterised and associated with species and drug specific loss of susceptibility.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [16]
The most significant MIC elevation is found for alterations involving the 1st and 5th amino acids (phenylalanine and serine) in the hot spot 1 regions of the FKS1 or FKS2 target genes.
“The most significant MIC elevation is found for alterations involving the 1st and 5th AA(F (phenylalanine) and S (serine)), respectively in the hot spot 1 regions of the FKS1 or FKS2 target genes (Table 1 and 2).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [16]

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Perlin DS, Balashov S, Park S. Role of glucan synthase subunit Fks1p in echinocandin resistance in Candida spp. ICAAC; Washington, D.C.: 2005. [Google Scholar]

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“albicans, and require a regulatory subunit encoded by RHO1 for activity [3,20,32,33].”
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Authors: Perlin, D. S.
Affiliations: Rutgers New Jersey Medical School (US)
Corresponding author: Perlin, David S.
ORCID: Perlin, David S.
Venue: Drug Resistance Updates
Publisher: Elsevier BV
Published: 2007-06
Volume: 10
Issue: 3
Pages: 121-130
ISSN: 1368-7646 (ISSN-L)
DOI: 10.1016/j.drup.2007.04.002
PMC: PMC2696280
OpenAlex: W1986481314
Cited by: 512
References: 81
Citations by year: 2026: 12 · 2025: 21 · 2024: 14 · 2023: 19 · 2022: 14 · 2021: 18 · 2020: 15 · 2019: 15 · 2018: 20 · 2017: 30 · 2016: 23 · 2015: 33 · 2014: 36 · 2013: 30 · 2012: 39
FWCI: 25.16
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Drug Resistance Updates (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Allergy and Infectious Diseases (R01AI069397)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: echinocandin resistance, antifungal resistance, beta-1,3-glucan synthase, FKS1, Candida, invasive fungal infections, minimum inhibitory concentration, amino acid substitutions, cross-resistance, fungal cell wall, molds
MeSH terms: Antifungal Agents, Candida albicans, Candidiasis, Glucosyltransferases, Humans, Membrane Proteins, Microbial Sensitivity Tests, Mutation, Mycoses, Amino Acid Substitution, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins, beta-Glucans, Echinocandins

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Resistance to echinocandin-class antifungal drugs.

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