title: Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen.
abstract: Therapeutic options for tuberculosis (TB) are limited and notoriously ineffective despite the wide variety of potent antibiotics available for treating other bacterial infections. We investigated an approach that enables an expansion of TB therapeutic strategies by using synergistic combinations of drugs. To achieve this, we devised a high-throughput synergy screen (HTSS) of chemical libraries having known pharmaceutical properties, including thousands that are clinically approved. Spectinomycin was used to test the concept that clinically available antibiotics with limited efficacy against Mycobacterium tuberculosis might be used for TB treatment when coadministered with a synergistic partner compound used as a sensitizer. Screens using Mycobacterium smegmatis revealed many compounds in our libraries that acted synergistically with spectinomycin. Among them, several families of antimicrobial compounds, including macrolides and azoles, were also synergistic against M. tuberculosis in vitro and in a macrophage model of M. tuberculosis infection. Strikingly, each sensitizer identified for synergy with spectinomycin uniquely enhanced the activities of other clinically used antibiotics, revealing a remarkable number of unexplored synergistic drug combinations. HTSS also revealed a novel activity for bromperidol, a butyrophenone used as an antipsychotic drug, which was discovered to be bactericidal and greatly enhanced the activities of several antibiotics and drug combinations against M. tuberculosis. Our results suggest that many compounds in the currently available pharmacopoeia could be readily mobilized for TB treatment, including disease caused by multi- and extensively drug-resistant strains for which there are no effective therapies.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón-García
authors.forename: Carol
authors.initials: C
authors.lastname: Ng
authors.forename: Hilary
authors.initials: H
authors.lastname: Anderson
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Chao
authors.forename: Xingji
authors.initials: X
authors.lastname: Zheng
authors.forename: Tom
authors.initials: T
authors.lastname: Pfeifer
authors.forename: Yossef
authors.initials: Y
authors.lastname: Av-Gay
authors.forename: Michel
authors.initials: M
authors.lastname: Roberge
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Thompson
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D000198:Spectinomycin / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D000198:Spectinomycin; D006220:Haloperidol; C006820:bromperidol