Could targeting bacterial metabolism reduce treatment times for tuberculosis?

New research has suggested that Mycobacterium tuberculosis alter their metabolism in order to survive exposure to antimicrobials and that targeting these metabolic changes could reduce the duration of tuberculosis (TB) therapy.

TB requires a long treatment regimen, often with poor compliance, and the slow killing of the bacteria increases the risk of tolerance and drug-resistance. In this article, the team, from Oregon State University (OR, USA), estimates that decreasing treatment times from 6 months to 3 weeks could reduce the issue of compliance, and that their latest research may be a key step towards this goal.

Lead author Luiz Bermudez (Oregon State University) commented: “Because of problems with compliance, you have resistance becoming more and more of an issue, and the second line of drugs is much more toxic than the first line of drugs.”

The researchers therefore investigated how M. tuberculosis prolongs its survival following exposure to antimicrobials. They utilized quantitative shotgun mass spectrometry to study the proteomic response of bacteria to the anti-TB drugs isoniazid, rifampicin, moxifloxacin, mefloquine and bedaquiline, discovering several pathways and enzymes associated with changes in metabolic state that appeared to prolong bacterial survival.

Bermudez explained: “When we looked at the enzymes carefully, we realized the enzymes being synthesized by the bacteria were enzymes connecting several different metabolic pathways. Then we came up with the idea that maybe what the bacteria were trying to do, in the presence of a bactericidal compound that was threatening their way of living, was use other ways to survive. One of the things we saw, for example, was a shift to an anaerobic metabolism, which makes a lot of drugs inactive and incapable of killing bacteria.”

The team went on to further investigate these proteins, discovering that overexpression of some of the identified proteins in the mycobacterial strain M. smegmatis extended bacterial survival when exposed to antimicrobials. In addition, the researchers observed that inactivation of the proteins in M. tuberculosis prevented metabolic changes and allowed rapid killing in vitro and in macrophages.

Bermudez stated: “The gene inactivation of some of these enzymes results in improved drug efficacy against M. tuberculosis. The identified proteins may provide powerful targets for development of synergistic drugs aimed to accelerate bacterial killing.”

This study is the first to identify these novel metabolic ‘escape pathways’, which the team hope could be targeted by drugs in order to reduce treatment times for TB. Bermudez concluded: “If we can use another compound that inhibits bacteria from shifting metabolic pathways, then we get a more reliable and desirable synergy of therapy. That might have a significant impact on reducing the time needed for therapy and improving compliance and, consequently, reducing the emergence of resistance.”

Sources: Danelishvili L, Shulzhenko N, Chinison JJJ et al. Mycobacterium tuberculosis proteome response to anti-tuberculosis compounds reveals metabolic “escape” pathways that prolong bacterial survival. Antimicrob. Agents. Chemother. doi:10.1128/AAC.00430-17. (2017) (Epub ahead of print)


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