N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis
UMass Chan AffiliationsDepartment of Microbiology and Physiological Systems
Bacterial Infections and Mycoses
Immunology of Infectious Disease
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AbstractThe rising incidence of antimicrobial resistance (AMR) makes it imperative to understand the underlying mechanisms. Mycobacterium tuberculosis (Mtb) is the single leading cause of death from a bacterial pathogen and estimated to be the leading cause of death from AMR. A pyrido-benzimidazole, 14, was reported to have potent bactericidal activity against Mtb. Here, we isolated multiple Mtb clones resistant to 14. Each had mutations in the putative DNA-binding and dimerization domains of rv2887, a gene encoding a transcriptional repressor of the MarR family. The mutations in Rv2887 led to markedly increased expression of rv0560c. We characterized Rv0560c as an S-adenosyl-L-methionine-dependent methyltransferase that N-methylates 14, abolishing its mycobactericidal activity. An Mtb strain lacking rv0560c became resistant to 14 by mutating decaprenylphosphoryl-beta-d-ribose 2-oxidase (DprE1), an essential enzyme in arabinogalactan synthesis; 14 proved to be a nanomolar inhibitor of DprE1, and methylation of 14 by Rv0560c abrogated this activity. Thus, 14 joins a growing list of DprE1 inhibitors that are potently mycobactericidal. Bacterial methylation of an antibacterial agent, 14, catalyzed by Rv0560c of Mtb, is a previously unreported mechanism of AMR.
SourceProc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4523-30. doi: 10.1073/pnas.1606590113. Epub 2016 Jul 18.Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/39981
Full author list omitted for brevity. For full list of authors see article.
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