Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline
Multidrug-resistant tuberculosis (MDR-TB), defined as resistance to the first-line drugs isoniazid and rifampin, is a growing source of global mortality and threatens global control of tuberculosis disease. The diarylquinoline bedaquiline has recently emerged as a highly efficacious drug against MDR-TB and kills Mycobacterium tuberculosis by inhibiting mycobacterial ATP synthase. However, the mechanisms underlying bedaquiline's efficacy against MDR-TB remain unknown. Here we investigate bedaquiline hyper-susceptibility in drug-resistant Mycobacterium tuberculosis using systems biology approaches. We discovered that MDR clinical isolates are commonly sensitized to bedaquiline. This hypersensitization is caused by several physiological changes induced by deficient catalase activity. These include enhanced accumulation of reactive oxygen species, increased susceptibility to DNA damage, induction of sensitizing transcriptional programs, and metabolic repression of several biosynthetic pathways. In this work we demonstrate how resistance-associated changes in bacterial physiology can mechanistically induce collateral antimicrobial drug sensitivity and reveal druggable vulnerabilities in antimicrobial resistant pathogens.
Authors
- Majid B. Shaikh
- Boatema Ofori-Anyinam (ORCID: https://orcid.org/0000-0002-8981-8188)
- Paul C. Blainey (ORCID: https://orcid.org/0000-0002-4889-8783)
- Shuyi Ma (ORCID: https://orcid.org/0000-0003-0783-1328)
- Courtney Grady (ORCID: https://orcid.org/0000-0003-0244-9816)
- Meagan Hamblin (ORCID: https://orcid.org/0000-0001-9989-9033)
- Gautam Mereddy
- Barry Li (ORCID: https://orcid.org/0000-0003-1102-561X)
- James J. Collins (ORCID: https://orcid.org/0000-0002-5560-8246)
- Avi Shah (ORCID: https://orcid.org/0000-0003-2822-9133)
- Jason H. Yang (ORCID: https://orcid.org/0000-0003-0921-4657)
- Navpreet Ranu (ORCID: https://orcid.org/0000-0001-5412-8200)
- Shou‐En Lu
- Miranda L Coldren
Institutions
- Rutgers, The State University of New Jersey (US)
- Broad Institute (US)
- Program for Appropriate Technology in Health (US)
- Infectious Disease Research Institute (US)
- University of Washington (US)
- EVERSANA (Canada) (CA)
- International Neuromodulation Society (US)
- Rutgers New Jersey Medical School (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1038/s41467-024-53933-8
- Citations
- 17
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 2.90
Funders
- National Science Foundation
- Burroughs Wellcome Fund
- University of Washington
- Broad Institute
- National Institutes of Health
- Defense Threat Reduction Agency
- Office of International Science and Engineering