ArticleProceedings of the National Academy of Sciences of the United States of America2016
N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 98 citations in OpenAlex.
- A Functional Metabolomics Framework to Track Microbiome Drug Metabolism.bioRxiv : the preprint server for biology · 2026Article
- Key Proteins and Enzymatic Mechanisms Underlying Drug Resistance in Mycobacterium tuberculosis.Advances in experimental medicine and biology · 2026Review
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- Thioquinazolinones as Antituberculosis Agents Targeting Phosphopantetheinyl Transferase.Journal of medicinal chemistry · 2025Article
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- Benzene Amide Ether Scaffold is Active against Non-replicating and IntracellularACS infectious diseases · 2023Article
- Synthesis and Structure-Activity Relationships of a New Class of Oxadiazoles Targeting DprE1 as Antitubercular Agents.ACS medicinal chemistry letters · 2023Article
- Gliotoxin and related metabolites as zinc chelators: implications and exploitation to overcome antimicrobial resistance.Essays in biochemistry · 2023Article
- Efficient biosynthesis of (R)-mandelic acid from styrene oxide by an adaptive evolutionary Gluconobacter oxydans STA.Biotechnology for biofuels and bioproducts · 2023Article
- Integrated genomics and chemical biology herald an era of sophisticated antibacterial discovery, from defining essential genes to target elucidation.Cell chemical biology · 2022Review
- Unraveling the mechanisms of intrinsic drug resistance inFrontiers in cellular and infection microbiology · 2022Review
- Transcriptional regulation and drug resistance inFrontiers in cellular and infection microbiology · 2022Review
- AC2P20 selectively killsRSC advances · 2021Article
- Characterizing the portability of phage-encoded homologous recombination proteins.Nature chemical biology · 2021Article
- Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.Nature communications · 2021Article
- TheFrontiers in cellular and infection microbiology · 2021Article
- Bioassay-Guided Interpretation of Antimicrobial Compounds in Kumu, a TCM Preparation FromFrontiers in pharmacology · 2021Article
- Morphological profiling of tubercle bacilli identifies drug pathways of action.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
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23 authors at 7 institutions in 4 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.