Journal article
Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance
Antimicrobial agents and chemotherapy, v 56(12), pp 6304-6309
Dec 2012
PMID: 23027185
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The echinocandins caspofungin, micafungin, and anidulafungin, inhibitors of cell wall β-1,3-glucan synthesis, were recently elevated to first-line agents for treating infections due to the azole-refractory yeast
Candida glabrata
. In
Candida albicans
, echinocandin resistance is strictly associated with mutations in Fks1, a large integral membrane protein and putative β-1,3-glucan synthase, while mutations in both Fks1 and its paralog Fks2 (but not Fks3) have been associated with resistance in
C. glabrata
. To further explore their function, regulation, and role in resistance,
C. glabrata
fks
genes were disrupted and subjected to mutational analysis, and their differential regulation was explored. An
fks1
Δ
fks2
Δ double disruptant was not able to be generated; otherwise, all three single and remaining two double disruptants displayed normal growth and echinocandin susceptibility, indicating Fks1-Fks2 redundancy. Selection on echinocandin-containing medium for resistant mutants was dependent on strain background: only
fks1
Δ and
fks1
Δ
fks3
Δ strains consistently yielded mutants exhibiting high-level resistance, all with Fks2 hot spot 1 mutations. Thus, Fks1-Fks2 redundancy attenuates the rate of resistance; further analysis showed that it also attenuates the impact of resistance-conferring mutations. Growth of the
fks1
Δ and, especially,
fks1
Δ
fks3
Δ strains was specifically susceptible to the calcineurin inhibitor FK506. Relatedly, FK506 addition or calcineurin gene
CMP2
disruption specifically reversed Fks2-mediated resistance of laboratory mutants and clinical isolates. RNA analysis suggests that transcriptional control is not the sole mechanism by which calcineurin modulates Fks2 activity.
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Details
- Title
- Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance
- Creators
- Santosh K Katiyar - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAAna Alastruey-Izquierdo - Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USAKelley R Healey - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAMichael E Johnson - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USADavid S Perlin - Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USAThomas D Edlind - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
- Publication Details
- Antimicrobial agents and chemotherapy, v 56(12), pp 6304-6309
- Publisher
- American Society for Microbiology; 1752 N St., N.W., Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000311052900029
- Scopus ID
- 2-s2.0-84869203438
- Other Identifier
- 991014877768504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy