title: SCY-078 Is Fungicidal against Candida Species in Time-Kill Studies.
abstract: SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis.In vitrosusceptibilities by broth microdilution, antifungal carryover, and time-kill dynamics were determined for three reference (ATCC) strains (Candida albicans90028,Candida parapsilosis90018, andCandida tropicalis750), a quality-control (QC) strain (Candida krusei6258), and four other strains (C. albicansMYA-2732, 64124, and 76485 andCandida glabrata90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16 times the MIC80, and FLU and VRC were evaluated at 4× MIC80The time to reach 50%, 90%, and 99.9% reduction in the number of CFUs from the starting inoculum was determined. Net change in the number of CFU per milliliter was used to determine 50% and 90% effective concentrations and maximum effect (EC50, EC90, andEmax, respectively). The SCY-078 MIC range was between 0.0625 and 1 μg/ml and generally similar to that of CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against seven isolates at ≥4× MIC (kill of ≥3 log10) and achieved a 1.7-log10reduction in CFU count/milliliter againstC. albicans90028. CASP behaved similarly against each isolate and achieved a 1.5-log10reduction in the number of CFU/milliliter againstC. albicans90028. Reductions of 50% in CFU count/milliliter were achieved rapidly (1 to 2.8 h); fungicidal endpoints were reached at 12.1 to 21.8 h at ≥4× MIC. EC90was reached at ∼5× MIC at each time point to 24 h. The EC50and EC90values were generally similar (8 to 24 h). Time-kill behavior of CASP was similar to that of SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity againstCandidaspp. and behaved comparably to CASP.
authors.affiliation: Scynexis, Inc., Jersey City, New Jersey, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Scorneaux
authors.affiliation: Scynexis, Inc., Jersey City, New Jersey, USA.
authors.forename: David
authors.initials: D
authors.lastname: Angulo
authors.affiliation: Scynexis, Inc., Jersey City, New Jersey, USA.
authors.forename: Katyna
authors.initials: K
authors.lastname: Borroto-Esoda
authors.affiliation: Case Western University, Cleveland, Ohio, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ghannoum
authors.affiliation: Scynexis, Inc., Jersey City, New Jersey, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peel
authors.affiliation: Scynexis, Inc., Jersey City, New Jersey, USA steve.wring@scynexis.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wring
mesh_terms: D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002175:Candida / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D041022:Candida tropicalis / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D000077336:Caspofungin; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology; D006027:Glycosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D014315:Triterpenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D006027:Glycosides; D055666:Lipopeptides; D014315:Triterpenes; D015725:Fluconazole; C569338:ibrexafungerp; D000077336:Caspofungin; D065819:Voriconazole
keywords: SCY-078