You are here

N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis.

TitleN-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2016
AuthorsWarrier T, Kapilashrami K, Argyrou A, Ioerger TR, Little D, Murphy KC, Nandakumar M, Park S, Gold B, Mi J, Zhang T, Meiler E, Rees M, Somersan-Karakaya S, De Francisco EPorras-, Martinez-Hoyos M, Burns-Huang K, Roberts J, Ling Y, Rhee KY, Mendoza-Losana A, Luo M, Nathan C
JournalProc Natl Acad Sci U S A
Volume113
Issue31
PaginationE4523-30
Date Published2016 Aug 02
ISSN1091-6490
Abstract

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.

DOI10.1073/pnas.1606590113
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27432954
PubMed Central IDPMC4978242
Grant ListU19 AI111143 / AI / NIAID NIH HHS / United States
R01 GM096056 / GM / NIGMS NIH HHS / United States
K08 AI108799 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 GM120570 / GM / NIGMS NIH HHS / United States