N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis. Academic Article uri icon


  • 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--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.

published proceedings

  • Proc Natl Acad Sci U S A

altmetric score

  • 6.1

author list (cited authors)

  • Warrier, T., Kapilashrami, K., Argyrou, A., Ioerger, T. R., Little, D., Murphy, K. C., ... Nathan, C. F.

citation count

  • 68

complete list of authors

  • Warrier, Thulasi||Kapilashrami, Kanishk||Argyrou, Argyrides||Ioerger, Thomas R||Little, David||Murphy, Kenan C||Nandakumar, Madhumitha||Park, Suna||Gold, Ben||Mi, Jianjie||Zhang, Tuo||Meiler, Eugenia||Rees, Mike||Somersan-Karakaya, Selin||Porras-De Francisco, Esther||Martinez-Hoyos, Maria||Burns-Huang, Kristin||Roberts, Julia||Ling, Yan||Rhee, Kyu Y||Mendoza-Losana, Alfonso||Luo, Minkui||Nathan, Carl F

publication date

  • August 2016