Abstract
The echinocandin antifungal drugs inhibit synthesis of the major fungal cell wall polysaccharide β(1,3)-glucan. Echinocandins have good efficacy against Candida albicans but reduced activity against other Candida species, in particular Candida parapsilosis and Candida guilliermondii. Treatment of Candida albicans with a sub-MIC level of caspofungin has been reported to cause a compensatory increase in chitin content and to select for sporadic echinocandin-resistant FKS1 point mutants that also have elevated cell wall chitin. Here we show that elevated chitin in response to caspofungin is a common response in various Candida species. Activation of chitin synthesis was observed in isolates of C. albicans, Candida tropicalis, C. parapsilosis, and C. guilliermondii and in some isolates of Candida krusei in response to caspofungin treatment. However, Candida glabrata isolates demonstrated no exposure-induced change in chitin content. Furthermore, isolates of C. albicans, C. krusei, C. parapsilosis, and C. guilliermondii which were stimulated to have higher chitin levels via activation of the calcineurin and protein kinase C (PKC) signaling pathways had reduced susceptibility to caspofungin. Isolates containing point mutations in the FKS1 gene generally had higher chitin levels and did not demonstrate a further compensatory increase in chitin content in response to caspofungin treatment. These results highlight the potential of increased chitin synthesis as a potential mechanism of tolerance to caspofungin for the major pathogenic Candida species.
Original language | English |
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Pages (from-to) | 146-154 |
Number of pages | 9 |
Journal | Antimicrobial Agents and Chemotherapy |
Volume | 57 |
Issue number | 1 |
Early online date | 22 Oct 2012 |
DOIs | |
Publication status | Published - Jan 2013 |
Bibliographical note
ACKNOWLEDGMENTSWe acknowledge the financial support of Gilead Sciences through a Ph.D. studentship for L.A.W. We also acknowledge research grants from the British Society for Antimicrobial Chemotherapy, the Wellcome Trust (grants 080088, 086827, and 075470), and the Ariadne Marie Curie Training Network.