Chemogenomic profiling predicts antifungal synergies.
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.
Jansen
Gregor
G
Department of Biochemistry, Faculty of Medicine, McGill University, Montréal, Québec, Canada. gregor.jansen@mcgill.ca
Lee
Anna Y
AY
Epp
Elias
E
Fredette
Amélie
A
Surprenant
Jamie
J
Harcus
Doreen
D
Scott
Michelle
M
Tan
Elaine
E
Nishimura
Tamiko
T
Whiteway
Malcolm
M
Hallett
Michael
M
Thomas
David Y
DY
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
D000935:Antifungal Agents; D015725:Fluconazole