title: Discovery of uracil-based histone deacetylase inhibitors able to reduce acquired antifungal resistance and trailing growth in Candida albicans.
abstract: Among fungal pathogens such as Candida albicans, acquired drug resistance has not been associated with plasmids or other transferable elements, but it is thought to involve primarily mutations and genetic or epigenetic phenomena. This prompted us to test some histone deacetylase inhibitors (HDACi) from our library, in combination with fluconazole, against C. albicans strains in vitro. Among the tested compounds, the two chloro-containing uracil-hydroxamates 1c and 1d showed a strong reduction of the MIC values on Candida strains that show the trailing growth effect. In this assay, 1c,d were more potent than SAHA, a well-known HDAC inhibitor, in reducing the Candida growth. More interestingly, 1c,d as well as SAHA were able to inhibit the fluconazole-induced resistance induction in Candida cultures.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. antonello.mai@uniroma1.it
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Gerald
authors.initials: G
authors.lastname: Brosch
authors.forename: Giovanna
authors.initials: G
authors.lastname: Simonetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Passariello
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Palamara
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014498:Uracil
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014498:Uracil; D015725:Fluconazole