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.