title: The efflux pump inhibitor timcodar improves the potency of antimycobacterial agents.
abstract: Previous studies indicated that inhibition of efflux pumps augments tuberculosis therapy. In this study, we used timcodar (formerly VX-853) to determine if this efflux pump inhibitor could increase the potency of antituberculosis (anti-TB) drugs against Mycobacterium tuberculosis in in vitro and in vivo combination studies. When used alone, timcodar weakly inhibited M. tuberculosis growth in broth culture (MIC, 19 μg/ml); however, it demonstrated synergism in drug combination studies with rifampin, bedaquiline, and clofazimine but not with other anti-TB agents. When M. tuberculosis was cultured in host macrophage cells, timcodar had about a 10-fold increase (50% inhibitory concentration, 1.9 μg/ml) in the growth inhibition of M. tuberculosis and demonstrated synergy with rifampin, moxifloxacin, and bedaquiline. In a mouse model of tuberculosis lung infection, timcodar potentiated the efficacies of rifampin and isoniazid, conferring 1.0 and 0.4 log10 reductions in bacterial burden in lung, respectively, compared to the efficacy of each drug alone. Furthermore, timcodar reduced the likelihood of a relapse infection when evaluated in a mouse model of long-term, chronic infection with treatment with a combination of rifampin, isoniazid, and timcodar. Although timcodar had no effect on the pharmacokinetics of rifampin in plasma and lung, it did increase the plasma exposure of bedaquiline. These data suggest that the antimycobacterial drug-potentiating activity of timcodar is complex and drug dependent and involves both bacterial and host-targeted mechanisms. Further study of the improvement of the potency of antimycobacterial drugs and drug candidates when used in combination with timcodar is warranted.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.affiliation: Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, New York, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Shoen
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Jones
authors.affiliation: Central New York Research Corporation, Veterans Affairs Medical Center, Syracuse, New York, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cynamon
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA Christopher_locher@hotmail.com.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Locher
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D011725:Pyridines; C494139:timcodar