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These compounds have no structural similarity to existing antifungal drugs. Three of the four compounds have fungicidal activity against<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida<\/jats:named-content>spp.,<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cryptococcus neoformans<\/jats:named-content>, and several dermatophytes, while one is fungicidal to<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Aspergillus fumigatus<\/jats:named-content>. 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<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida<\/jats:named-content>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<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Saccharomyces cerevisiae<\/jats:named-content>mutants. We identified mutants that are both hypersensitive and resistant. Using FunSpec, the hypersensitive mutants and a resistant<jats:italic>ace2<\/jats:italic>mutant clustered within a category of genes related directly or indirectly to mitochondrial functions. In<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida albicans<\/jats:named-content>, 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.<\/jats:p>","DOI":"10.1128\/aac.00477-12","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T05:39:27Z","timestamp":1339479567000},"page":"4630-4639","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":25,"title":["Amino Acid-Derived 1,2-Benzisothiazolinone Derivatives as Novel Small-Molecule Antifungal Inhibitors: Identification of Potential Genetic Targets"],"prefix":"10.1128","volume":"56","author":[{"given":"Deepu","family":"Alex","sequence":"first","affiliation":[{"name":"Georgetown University Medical Center, Washington, DC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francoise","family":"Gay-Andrieu","sequence":"additional","affiliation":[{"name":"Georgetown University Medical Center, Washington, DC, USA"},{"name":"Nantes Atlantique Universities, EA1155-IICiMed, Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jared","family":"May","sequence":"additional","affiliation":[{"name":"Georgetown University Medical Center, Washington, DC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linta","family":"Thampi","sequence":"additional","affiliation":[{"name":"Georgetown University Medical Center, Washington, DC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dengfeng","family":"Dou","sequence":"additional","affiliation":[{"name":"Wichita State University, Department of Chemistry, Wichita, Kansas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aileen","family":"Mooney","sequence":"additional","affiliation":[{"name":"Georgetown University Medical Center, Washington, DC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Groutas","sequence":"additional","affiliation":[{"name":"Wichita State University, Department of Chemistry, Wichita, Kansas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Calderone","sequence":"additional","affiliation":[{"name":"Georgetown University Medical Center, Washington, DC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","first-page":"331","volume-title":"Candida and candidiasis","author":"Alex D","year":"2012","unstructured":"AlexD CalderoneR LiD. 2012. 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