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dc.contributor.authorAlex, Deepu
dc.contributor.authorGay-Andrieu, Francoise
dc.contributor.authorMay, Jared
dc.contributor.authorThampi, Linta
dc.contributor.authorDou, Dengfeng
dc.contributor.authorMooney, Aileen
dc.contributor.authorGroutas, William C.
dc.contributor.authorCalderone, Richard
dc.identifier.citationAlex, Deepu; Gay-Andrieu, Francoise; May, Jared; Thampi, Linta; Dou, Dengfeng; Mooney, Aileen; Groutas, William C.; Calderone, Richard. 2012. Amino acid-derived 1,2-benzisothiazolinone derivatives as novel small-molecule antifungal inhibitors: identification of potential genetic targets. Antimicrobial Agents and Chemotherapy, v.56 no.9 pp.4630-4639en_US
dc.descriptionClick on the DOI link to access the article (may not be free).en_US
dc.description.abstractWe have identified four synthetic compounds (DFD-VI-15, BD-I-186, DFD-V-49, and DFD-V-66) from an amino acid-derived 1,2-benzisothiazolinone (BZT) scaffold that have reasonable MIC50 values against a panel of fungal pathogens. These compounds have no structural similarity to existing antifungal drugs. Three of the four compounds have fungicidal activity against Candida spp., Cryptococcus neoformans, and several dermatophytes, while one is fungicidal to Aspergillus fumigatus. The kill rates of our compounds are equal to those in clinical usage. The BZT compounds remain active against azole-, polyene-, and micafungin-resistant strains of Candida spp. A genetics-based approach, along with phenotype analysis, was used to begin mode of action (MOA) studies of one of these compounds, DFD-VI-15. The genetics-based screen utilized a homozygous deletion collection of approximately 4,700 Saccharomyces cerevisiae mutants. We identified mutants that are both hypersensitive and resistant. Using FunSpec, the hypersensitive mutants and a resistant ace2 mutant clustered within a category of genes related directly or indirectly to mitochondrial functions. In Candida albicans, the functions of the Ace2p transcription factor include the regulation of glycolysis. Our model is that DFD-VI-15 targets a respiratory pathway that limits energy production. Supporting this hypothesis are phenotypic data indicating that DFD-VI-15 causes increased cell-reactive oxidants (ROS) and a decrease in mitochondrial membrane potential. Also, the same compound has activity when cells are grown in a medium containing glycerol (mitochondrial substrate) but is much less active when cells are grown anaerobically.en_US
dc.publisherAmerican Society of Microbiologyen_US
dc.relation.ispartofseriesAntimicrobial Agents and Chemotherapy;v.56 no.9
dc.subjectin-vitro activitiesen_US
dc.subjectfluconazole susceptibilityen_US
dc.subjectmitochondrial dysfunctionen_US
dc.subjectreduced susceptibilityen_US
dc.subjectresistance mechanismsen_US
dc.subjectinvasive candidiasisen_US
dc.subjectinfected patientsen_US
dc.subjectfungal pathogenen_US
dc.titleAmino acid-derived 1,2-benzisothiazolinone derivatives as novel small-molecule antifungal inhibitors: identification of potential genetic targetsen_US

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