title: Chemogenomic profiling predicts antifungal synergies.
abstract: Chemotherapies, HIV infections, and treatments to block organ transplant rejection are creating a population of immunocompromised individuals at serious risk of systemic fungal infections. Since single-agent therapies are susceptible to failure due to either inherent or acquired resistance, alternative therapeutic approaches such as multi-agent therapies are needed. We have developed a bioinformatics-driven approach that efficiently predicts compound synergy for such combinatorial therapies. The approach uses chemogenomic profiles in order to identify compound profiles that have a statistically significant degree of similarity to a fluconazole profile. The compounds identified were then experimentally verified to be synergistic with fluconazole and with each other, in both Saccharomyces cerevisiae and the fungal pathogen Candida albicans. Our method is therefore capable of accurately predicting compound synergy to aid the development of combinatorial antifungal therapies.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, McGill University, Montréal, Québec, Canada. gregor.jansen@mcgill.ca
authors.forename: Gregor
authors.initials: G
authors.lastname: Jansen
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Lee
authors.forename: Elias
authors.initials: E
authors.lastname: Epp
authors.forename: Amélie
authors.initials: A
authors.lastname: Fredette
authors.forename: Jamie
authors.initials: J
authors.lastname: Surprenant
authors.forename: Doreen
authors.initials: D
authors.lastname: Harcus
authors.forename: Michelle
authors.initials: M
authors.lastname: Scott
authors.forename: Elaine
authors.initials: E
authors.lastname: Tan
authors.forename: Tamiko
authors.initials: T
authors.lastname: Nishimura
authors.forename: Malcolm
authors.initials: M
authors.lastname: Whiteway
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.forename: David Y
authors.initials: DY
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D019295:Computational Biology; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D025141:Drug Resistance, Fungal / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015725:Fluconazole / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole