4.5 Article

CRISPRi chemical genetics and comparative genomics identify genes mediating drug potency in Mycobacterium tuberculosis

Journal

NATURE MICROBIOLOGY
Volume 7, Issue 6, Pages 766-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41564-022-01130-y

Keywords

-

Categories

Funding

  1. Harvey L. Karp Postdoctoral Fellowship
  2. Potts Memorial Foundation
  3. Bill and Melinda Gates Foundation [INV-010616, INV-004761]
  4. Department of Defense [PR192421]
  5. Robertson Therapeutic Development Fund
  6. NIH Shared Instrumentation Grant [S10-OD023524]
  7. NIH/NIAID New Innovator Award [1DP2AI144850-01]
  8. Bill and Melinda Gates Foundation [INV-004761] Funding Source: Bill and Melinda Gates Foundation

Ask authors/readers for more resources

This study utilized a CRISPR interference chemical-genetics platform to uncover various drug resistant mechanisms in Mycobacterium tuberculosis (Mtb) and identified a potential new drug for treating tuberculosis.
Mycobacterium tuberculosis (Mtb) infection is notoriously difficult to treat. Treatment efficacy is limited by Mtb's intrinsic drug resistance, as well as its ability to evolve acquired resistance to all antituberculars in clinical use. A deeper understanding of the bacterial pathways that influence drug efficacy could facilitate the development of more effective therapies, identify new mechanisms of acquired resistance, and reveal overlooked therapeutic opportunities. Here we developed a CRISPR interference chemical-genetics platform to titrate the expression of Mtb genes and quantify bacterial fitness in the presence of different drugs. We discovered diverse mechanisms of intrinsic drug resistance, unveiling hundreds of potential targets for synergistic drug combinations. Combining chemical genetics with comparative genomics of Mtb clinical isolates, we further identified several previously unknown mechanisms of acquired drug resistance, one of which is associated with a multidrug-resistant tuberculosis outbreak in South America. Lastly, we found that the intrinsic resistance factor whiB7 was inactivated in an entire Mtb sublineage endemic to Southeast Asia, presenting an opportunity to potentially repurpose the macrolide antibiotic clarithromycin to treat tuberculosis. This chemical-genetic map provides a rich resource to understand drug efficacy in Mtb and guide future tuberculosis drug development and treatment. Combined CRISPRi chemical genetics and comparative genomics reveal Mycobacterium tuberculosis drug resistance mechanisms and a potential opportunity to repurpose clarithromycin to treat tuberculosis due to inactivation of the whiB7 resistance factor in an entire Mtb sublineage.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available