title: Elevated chitin content reduces the susceptibility of Candida species to caspofungin.
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.
authors.affiliation: Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Walker
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
authors.forename: Carol A
authors.initials: CA
authors.lastname: Munro
mesh_terms: D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002175:Candida / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D000077336:Caspofungin; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D002686:Chitin / Q000819:agonists / Q000096:biosynthesis*; D025141:Drug Resistance, Fungal / Q000187:drug effects / Q000235:genetics*; D054714:Echinocandins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055666:Lipopeptides; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D002686:Chitin; D005964:Glucosyltransferases; D011493:Protein Kinase C; D019703:Calcineurin; D000077336:Caspofungin