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Rutgers: Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline.

Writer's picture: Ray SullivanRay Sullivan

Updated: Feb 2




The growing threat of multidrug-resistant tuberculosis (MDR-TB) is a major public health concern.  Tuberculosis still ranks among the world’s deadliest infectious diseases, killing more than 1.5 million people annually.  Bedaquiline is a highly effective drug against MDR-TB, but the mechanisms underlying bedaquiline's efficacy against MDR-TB were unknown, until now.  Jason Yang is an Assistant Professor and Chancellor Scholar in the Microbiology, Biochemistry and Molecular Genetics Department and Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens.  He is also this year’s Theobald Smith Society Young Investigator Awardee.  Jason’s lab tested the following hypotheses:


1. Isoniazid-resistant and MDR clinical isolates will exhibit increased sensitivity to bedaquiline.

2. Deficiencies in mycobacterial catalase-peroxidase (KatG) catalase activity will directly sensitize Mycobacterium tuberculosis to bedaquiline.

3. Isoniazid-resistant and MDR clinical strains harboring a KatG S315T mutation will be hypersusceptible to reactive oxygen species due to deficient catalase activity.

4. Deficiencies in catalase activity will result in increased oxidative cellular damage in response to bedaquiline treatment.

5. Altered induction of transcriptional programs in catalase activity-deficient cells will contribute to bedaquiline susceptibility.

6. Bedaquiline-induced defects in folate biosynthesis will contribute to bedaquiline hyper-susceptibility in drug-resistant M. tuberculosis.

 

They found bedaquiline hyper-susceptibility is common in MDR M. tuberculosis clinical isolates, including those with mycobacterial catalase-peroxidase S315T mutations.  Deficiencies in catalase activity, common in multidrug-resistant and isoniazid-resistant M. tuberculosis strains, sensitize these drug-resistant strains to the ATP synthase inhibitor bedaquiline through several mechanisms, including increased reactive oxygen species accumulation, impaired DNA repair, altered transcriptional programs, and metabolic repression of folate biosynthesis.  By understanding the mechanisms that increase susceptibility to bedaquiline, researchers can explore new therapeutic approaches that enhance the efficacy of existing drugs or develop novel agents that exploit these vulnerabilities.


Ofori-Anyinam B, Hamblin M, Coldren ML, Li B, Mereddy G, Shaikh M, Shah A, Grady C, Ranu N, Lu S, Blainey PC, Ma S, Collins JJ, Yang JH. Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline. Nat Commun. 2024 Nov 13;15(1):9792. doi: 10.1038/s41467-024-53933-8. PMID: 39537610; PMCID: PMC11561320.  https://www.nature.com/articles/s41467-024-53933-8

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