3 years ago

Combinations of respiratory chain inhibitors have enhanced bactericidal activity against Mycobacterium tuberculosis.

Tanya Parish, Bryan J Berube
As an obligate aerobe Mycobacterium tuberculosis uses its electron-transport chain (ETC) to produce energy via oxidative phosphorylation. This pathway has recently garnered a lot of attention and is a target for several new anti-mycobacterials. We tested the respiratory adaptation of M. tuberculosis to phenoxy alkyl benzimidazoles (PABs), compounds proposed to target QcrB, a component of the cytochrome bc1 complex. We show M. tuberculosis is able to reroute its ETC to provide temporary resistance to PABs. However, combination treatment of PAB with agents targeting other components of the electron-transport chain overcomes this respiratory flexibility. PAB in combination with clofazimine resulted in synergistic killing of M. tuberculosis under both replicating and non-replicating conditions. PABs in combination with bedaquiline demonstrated antagonism at early time-points, particularly in non-replicating conditions. However, this antagonistic effect disappeared within three weeks, when PAB/BDQ combinations became highly bactericidal; in some cases, were better than either drug alone. This study highlights the potential for combination treatment targeting the ETC and supports the development of PABs as part of a novel drug regimen against M. tuberculosis.

Publisher URL: http://doi.org/10.1128/AAC.01677-17

DOI: 10.1128/AAC.01677-17

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.