title: In vitro activity of a Hos2 deacetylase inhibitor, MGCD290, in combination with echinocandins against echinocandin-resistant Candida species.
abstract: MGCD290, a Hos2 fungal histone deacetylase inhibitor, showed modest activity when tested alone (MIC range, 0.12-4 μg/mL; MIC50/90, 0.5/4 μg/mL) against Candida glabrata (n=15; 14 fks mutants; 5 also fluconazole resistant), Candida albicans (8 fks mutants; 2 also fluconazole resistant), Candida tropicalis (4 fks mutants), and Candida krusei (3 fks mutants). However, MGCD290 showed synergy or partial synergy for 33.3%, 30.1%, 36.7%, and 80.0% of the isolates when tested with anidulafungin, caspofungin, micafungin, and fluconazole, respectively. Favorable interactions were achieved with low concentrations of MGCD290 (0.015-0.25 μg/mL), and categorical shifts were observed in 2 of 8 (25.0%) isolates of C. albicans and 2 of 3 (66.7%) isolates of C. krusei and in 4 of the 5 (80.0%) fluconazole-resistant isolates of C. glabrata. MGCD290 exerts a distinctly favorable influence on the MICs of fluconazole and the echinocandins, resulting in conversion from resistance to susceptibility regardless of fks mutations.
authors.affiliation: University of Iowa College of Medicine, Iowa City, IA, USA; JMI Laboratories, North Liberty, IA, USA. Electronic address: michael-pfaller@jmilabs.com.
authors.forename: M A
authors.initials: MA
authors.lastname: Pfaller
authors.affiliation: JMI Laboratories, North Liberty, IA, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Rhomberg
authors.affiliation: JMI Laboratories, North Liberty, IA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Messer
authors.affiliation: JMI Laboratories, North Liberty, IA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Castanheira
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects*; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D004791:Enzyme Inhibitors; D015725:Fluconazole
keywords: Antifungal susceptibility; Candida; Echinocandins