NDLI: Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance

Content Provider	PubMed Central
Author	Katiyar, Santosh K. Ana, Alastruey-izquierdo Healey, Kelley R. Johnson, Michael E. Perlin, David S. Edlind, Thomas D.
Copyright Year	2012
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 fks1Δ fks2Δ 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 fks1Δ and fks1Δ fks3Δ 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 fks1Δ and, especially, fks1Δ fks3Δ 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.
Related Links	http://dx.doi.org/10.1128/aac.00813-12
Ending Page	6309
Page Count	6
Starting Page	6304
File Format	PDF
ISSN	00664804
e-ISSN	10986596
Journal	Antimicrobial Agents and Chemotherapy
Issue Number	12
Volume Number	56
Language	English
Publisher	American Society for Microbiology
Publisher Date	2012-12-01
Access Restriction	Open
Rights Holder	American Society for Microbiology
Subject Keyword	Pharmacology (medical) Pharmacology Infectious Diseases Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Pharmacology Pharmacology (medical)

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