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


MeSH Major

  • Adenosine Triphosphate
  • Gene Expression Regulation, Bacterial
  • Macrophages
  • Mycobacterium tuberculosis
  • Nitrates
  • Nitrites
  • Oxygen


  • 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-β-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.

publication date

  • August 2, 2016



  • Academic Article



  • eng

PubMed Central ID

  • PMC4978242

Digital Object Identifier (DOI)

  • 10.1073/pnas.1606590113

PubMed ID

  • 27432954

Additional Document Info

start page

  • E4523

end page

  • 30


  • 113


  • 31