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N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsDocument Type
Journal ArticlePublication Date
2016-08-02Keywords
antimicrobial resistancearabinogalactan synthesis
methyltransferase
transcription factor
Bacterial Infections and Mycoses
Bacteriology
Immunology of Infectious Disease
Metadata
Show full item recordAbstract
The 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.Source
Proc 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 siteDOI
10.1073/pnas.1606590113Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39981PubMed ID
27432954Notes
Full author list omitted for brevity. For full list of authors see article.
Related Resources
Link to Article in PubMedRights
Freely available online through the PNAS open access option.
ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1606590113