Warrier, ThulasiMendoza Losana, Alfonso2023-11-102023-11-102016-07-18Warrier, T., Kapilashrami, K., Argyrou, A., Ioerger, T. R., Little, D., Murphy, K. C., Nandakumar, M., Park, S., Gold, B., Mi, J., Zhang, T., Meiler, E., Rees, M., Somersan-Karakaya, S., Porras-De Francisco, E., Martinez-Hoyos, M., Burns-Huang, K., Roberts, J., Ling, Y., … Nathan, C. F. (2016). N -methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences, 113 (31), E4523–E45300027-8424https://hdl.handle.net/10016/38832The 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.eng© The authorsAtribución-NoComercial-SinDerivadas 3.0 EspañaAntimicrobial resistanceTranscription factorMethyltransferaseArabinogalactan synthesisresearch articleBiología y Biomedicinahttps://doi.org/10.1073/pnas.1606590113open access4523314530PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA113AR/0000030706