Changes in the proteome of Candida albicans in response to azole, polyene, and echinocandin antifungal agents.
The yeast Candida albicans is an opportunistic human fungal pathogen and the cause of superficial and systemic infections in immunocompromised patients. The classes of antifungal agents most commonly used to treat Candida infections are the azoles, polyenes, and echinocandins. In the present study, we identified changes in C. albicans protein abundance using two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectroscopy following exposure to representatives of the azole (ketoconazole), polyene (amphotericin B), and echinocandin (caspofungin) antifungals in an effort to elucidate the adaptive responses to these classes of antifungal agents. We identified 39 proteins whose abundance changed in response to ketoconazole exposure. Some of these proteins are involved in ergosterol biosynthesis and are associated with azole resistance. Exposure to amphotericin B altered the abundance of 43 proteins, including those associated with oxidative stress and osmotic tolerance. We identified 50 proteins whose abundance changed after exposure to caspofungin, including enzymes involved in cell wall biosynthesis and integrity, as well as the regulator of beta-1,3-glucan synthase activity, Rho1p. Exposure to caspofungin also increased the abundance of the proteins involved in oxidative and osmotic stress. The common adaptive responses shared by all three antifungal agents included proteins involved in carbohydrate metabolism. Some of these antifungal-responsive proteins may represent potential targets for the development of novel therapeutics that could enhance the antifungal activities of these drugs.
Department of Clinical Pharmacy, Colleges of Pharmacy and Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Christopher F
CF
Hoehamer
Edwin D
ED
Cummings
George M
GM
Hilliard
P David
PD
Rogers
D000222:Adaptation, Physiological / Q000187:drug effects; D000666:Amphotericin B / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology*; D000077336:Caspofungin; D025141:Drug Resistance, Fungal / Q000502:physiology*; D054714:Echinocandins / Q000627:therapeutic use; D015180:Electrophoresis, Gel, Two-Dimensional; D004875:Ergosterol / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use; D055666:Lipopeptides; D018384:Oxidative Stress / Q000187:drug effects; D020543:Proteome / Q000187:drug effects* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014882:Water-Electrolyte Balance / Q000187:drug effects
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D020543:Proteome; D000666:Amphotericin B; D000077336:Caspofungin; D007654:Ketoconazole; D004875:Ergosterol