The Efflux Pump Inhibitor Timcodar Improves the Potency of Antimycobacterial Agents

Abstract

bPrevious 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 g/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 g/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 log 10 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.

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

“…Therefore, plasma drug concentrations of new drugs such as bedaquiline and delamanid will receive more attention in future studies as well as in daily practice. Also, in cases of off-label use or in studies evaluating the bactericidal activity of drug combinations, information on drug exposure is helpful to explain treatment outcome (24)(25)(26).…”

Targeting Efflux Pumps to Overcome Antifungal Drug Resistance

“…The approach of inhibiting transporters in order to overcome drug resistance is currently being applied to the bacterial pathogens Pseudomonas aeruginosa, future science group Targeting efflux pumps to overcome antifungal drug resistance Review Escherichia coli and Mycobacterium tuberculosis [22,23]. For example, the efflux pump inhibitor timcodar has been shown to increase the potency of the antituberculosis drugs rifampin and isoniazid toward M. tuberculosis in both in vitro and in vivo combination studies even though its precise mechanism of action is unknown [24]. The resistance-nodulation-division family of efflux pumps has received particular attention in P. aeruginosa and E. coli [25].…”

Diversity and evolution of drug resistance mechanisms in <em>Mycobacterium tuberculosis</em>

“… 79 These results occur when EPIs act as a single drug such as an SQ109 inhibitor, or enhances the efficacy of certain drug combinations such as timcodar. 80 , 81 More recently, Kumar et al 82 found that synthesis and design of hybrid EPIs by fusion of Verapamil™ with phenothiazines enhances inhibition of efflux pumps and may enable identification of novel molecules with a high efficacy for killing MTB.…”