Journal article
Cyclic AMP Signaling Pathway Modulates Susceptibility of Candida Species and Saccharomyces cerevisiae to Antifungal Azoles and Other Sterol Biosynthesis Inhibitors
Antimicrobial agents and chemotherapy, v 47(10), pp 3195-3201
Oct 2003
PMID: 14506030
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Azoles are widely used antifungals; however, their efficacy is compromised by fungistatic activity and selection of resistant strains during treatment. Recent studies demonstrated roles for the protein kinase C and calcium signaling pathways in modulating azole activity. Here we explored a role for the signaling pathway mediated by cyclic AMP (cAMP), which is synthesized by the regulated action of adenylate cyclase (encoded by
CDC35
in
Candida albicans
and
CYR1
in
Saccharomyces cerevisiae
) and cyclase-associated protein (encoded by
CAP1
and
SRV2
, respectively). Relative to wild-type strains,
C. albicans
and
S. cerevisiae
strains mutated in these genes were hypersusceptible to fluconazole (>4- to >16-fold-decreased 48-h MIC), itraconazole (>8- to >64-fold), or miconazole (16- to >64-fold). Similarly, they were hypersusceptible to terbinafine and fenpropimorph (2- to >16-fold), which, like azoles, inhibit sterol biosynthesis. Addition of cAMP to the medium at least partially reversed the hypersusceptibility of Ca-
cdc35
and Sc-
cyr1
-
2
mutants. An inhibitor of mammalian adenylate cyclase, MDL-12330A, was tested in combination with azoles; a synergistic effect was observed against azole-susceptible and -resistant strains of
C. albicans
and five of six non-
C. albicans Candida
species. Analysis of cAMP levels after glucose induction in the presence and absence of MDL-12330A confirmed that it acts by inhibiting cAMP synthesis in yeast. RNA analysis suggested that a defect in azole-dependent upregulation of the multidrug transporter gene
CDR1
contributes to the hypersusceptibility of the Ca-
cdc35
mutant. Our results implicate cAMP signaling in the yeast azole response; compounds similar to MDL-12330A may be useful adjuvants in azole therapy.
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Details
- Title
- Cyclic AMP Signaling Pathway Modulates Susceptibility of Candida Species and Saccharomyces cerevisiae to Antifungal Azoles and Other Sterol Biosynthesis Inhibitors
- Creators
- Pooja Jain - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129Indira Akula - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129Thomas Edlind - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129
- Publication Details
- Antimicrobial agents and chemotherapy, v 47(10), pp 3195-3201
- Publisher
- American Society for Microbiology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000185612600026
- Scopus ID
- 2-s2.0-0141924879
- Other Identifier
- 991014878142104721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy