Common heart drug may boost TB medicines and block resistance

Bedaquiline has become a cornerstone of new treatment regimens for drug-resistant tuberculosis, but clinicians and researchers worry because bedaquiline-resistant strains of Mycobacterium tuberculosis are emerging. The most common path to clinical bedaquiline resistance is not a change in the drug target ATP synthase but an increase in activity of a bacterial pump, the MmpS5L5 efflux pump, caused by mutations that inactivate the transcriptional repressor Rv0678. In clear, focused work led by Gregory M. Cook, researchers set out to define exactly how much the MmpS5L5 pump contributes to resistance and to test whether a widely used drug, verapamil, could block that pump and restore the potency of bedaquiline and related drugs. The team also looked at norverapamil, verapamil’s main metabolite, to see whether a version of the drug with reduced calcium channel effects could still help. The study was built around the idea that a drug that inhibits MmpS5L5 could both improve treatment and help prevent the development of resistance to bedaquiline and other affected medicines.

Using microbiological and biochemical approaches, the team showed that MmpS5L5 reduces susceptibility to a set of important antitubercular compounds. Specifically, the pump lowered bacterial sensitivity to bedaquiline and the newer, more potent derivative TBAJ-876, as well as to clofazimine and the DprE1 inhibitors PBTZ-169 and OPC-167832. The increased resistance seen in strains with Rv0678 mutations was traced entirely to higher MmpS5L5 activity, underscoring the pump’s central role. Turning to verapamil, a drug best known as a calcium channel inhibitor that has been observed to potentiate bedaquiline and clofazimine, the authors found that verapamil enhanced the activity of multiple diverse MmpS5L5 substrates. Importantly, biochemical tests argued against a previously proposed mechanism: verapamil did not act by collapsing the protonmotive force that powers MmpS5L5. Instead, the data are consistent with verapamil directly inhibiting the function of the MmpS5L5 pump. Norverapamil, which has greatly reduced calcium channel activity, showed equal potency in reducing resistance to MmpS5L5 substrates.

These results point to practical ways to make current TB drugs work better and to slow the spread of resistance. If a safe, inexpensive drug like verapamil — or its metabolite norverapamil — can inhibit MmpS5L5 in patients, it could enhance the effectiveness of bedaquiline, TBAJ-876, clofazimine, PBTZ-169, OPC-167832 and possibly other substrates of the same pump. That dual effect — improving killing of Mycobacterium tuberculosis and preventing the selection of resistant mutants driven by Rv0678 mutations — makes pharmacological inhibition of MmpS5L5 a promising strategy. The work led by Gregory M. Cook not only identifies verapamil and norverapamil as candidate adjuncts for bedaquiline-based regimens but also provides a strong rationale to search for additional, specific MmpS5L5 inhibitors that could be developed as companion drugs to protect and extend the lifespan of vital antitubercular therapies.