title: Mechanisms of echinocandin antifungal drug resistance.
abstract: Fungal infections due to Candida and Aspergillus species cause extensive morbidity and mortality, especially among immunosuppressed patients, and antifungal therapy is critical to patient management. Yet only a few drug classes are available to treat invasive fungal diseases, and this problem is compounded by the emergence of antifungal resistance. Echinocandin drugs are the preferred choice to treat candidiasis. They are the first cell wall-active agents and target the fungal-specific enzyme glucan synthase, which catalyzes the biosynthesis of β-1,3-glucan, a key cell wall polymer. Therapeutic failures occur rarely among common Candida species, with the exception of Candida glabrata, which is frequently multidrug resistant. Echinocandin resistance in susceptible species is always acquired during therapy. The mechanism of resistance involves amino acid changes in hot-spot regions of Fks subunits of glucan synthase, which decrease the sensitivity of the enzyme to drug. Cellular stress response pathways lead to drug adaptation, which promotes the formation of resistant fks strains. Clinical factors promoting echinocandin resistance include empiric therapy, prophylaxis, gastrointestinal reservoirs, and intra-abdominal infections. A better understanding of the echinocandin-resistance mechanism, along with cellular and clinical factors promoting resistance, will facilitate more effective strategies to overcome and prevent echinocandin resistance.
authors.affiliation: New Jersey Medical School, Rutgers Biomedical and Health Sciences, Public Health Research Institute, Newark, New Jersey.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
mesh_terms: D000935:Antifungal Agents / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D041221:Candida glabrata / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D025141:Drug Resistance, Fungal; D054714:Echinocandins / Q000627:therapeutic use*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D013045:Species Specificity; D047071:beta-Glucans / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D047071:beta-Glucans; C033363:beta-1,3-glucan; D005964:Glucosyltransferases; C040232:glucan synthase
keywords: FKS; caspofungin; chitin synthase; echinocandin; glucan synthase; micafungin