Department of Microbiology and Physiological Systems
Bacterial Infections and Mycoses | Bacteriology | Immunology of Infectious Disease
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.
antimicrobial resistance, arabinogalactan synthesis, methyltransferase, transcription factor
Rights and Permissions
Freely available online through the PNAS open access option.
DOI of Published Version
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 site
Proceedings of the National Academy of Sciences of the United States of America
Murphy, Kenan C. and Nathan, Carl F., "N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis" (2016). Open Access Articles. 2790.