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

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dc.contributor.authorWarrier, Thulasi
dc.contributor.authorMendoza Losana, Alfonso
dc.date.accessioned2023-11-10T16:37:10Z
dc.date.available2023-11-10T16:37:10Z
dc.date.issued2016-07-18
dc.description.abstractThe 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.en
dc.description.sponsorshipWe are grateful to Tanya Parish at the Infectious Disease Research Institute for the Mtb strain deficient in rv0560c (Arv0560c) and its wild-type background strain, Mtb H37Rv London Pride (LP); and Stewart Cole at École Polytechnique Fédérale de Lausanne for Mtb strains carrying point mutations in DprE1. We thank James Sacchettini at Texas A&M University, Christopher Sassetti at University of Massachusetts Medical School, and Gurdyal Besra at University of Birmingham for guidance and support. We thank George Sukenick at the NMR facility at MSKCC and Jenny Xiang at the Genomics Core Facility at Weill Cornell Medicine for help with experimental setup and data collection. We are grateful for the help of Raquel Fernandez in synthesizing 14-IA and for the support of the TB unit in DDW-GlaxoSmithKline. Research performed in the M.L. laboratory was supported by NIGMS (2R01GM096056) and NIH/NCI Cancer Center Support Grant 5P30 CA008748-44. Work at Weill Cornell Medicine was supported by grants from the Bill & Melinda Gates Foundation (OPP1024029) and NIH (U19 AI111143-01, Tri-Institutional TB Research Unit). The Department of Microbiology & Immunology is supported by the William Randolph Hearst Trust.en
dc.identifier.bibliographicCitationWarrier, 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–E4530en
dc.identifier.doihttps://doi.org/10.1073/pnas.1606590113
dc.identifier.issn0027-8424
dc.identifier.publicationfirstpage4523es
dc.identifier.publicationissue31es
dc.identifier.publicationlastpage4530es
dc.identifier.publicationtitlePROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAen
dc.identifier.publicationvolume113es
dc.identifier.urihttps://hdl.handle.net/10016/38832
dc.identifier.uxxiAR/0000030706
dc.language.isoenges
dc.publisherNational Academy of Scienceses
dc.rights© The authorses
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España*
dc.rights.accessRightsopen accesses
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.subject.ecienciaBiología y Biomedicinaes
dc.subject.otherAntimicrobial resistanceen
dc.subject.otherTranscription factoren
dc.subject.otherMethyltransferaseen
dc.subject.otherArabinogalactan synthesisen
dc.titleN-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosisen
dc.typeresearch article*
dc.type.hasVersionVoR*
dspace.entity.typePublication
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