N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis
| Autor: | Eugenia Meiler, Minkui Luo, Madhumitha Nandakumar, Kenan C. Murphy, Thulasi Warrier, Mike Rees, Ben Gold, Carl Nathan, Argyrides Argyrou, Kyu Y. Rhee, Thomas R. Ioerger, Julia Roberts, Kanishk Kapilashrami, Tuo Zhang, Selin Somersan-Karakaya, Alfonso Mendoza-Losana, Yan Ling, David Little, María Martínez-Hoyos, Kristin Burns-Huang, Jianjie Mi, Suna Park, Esther Porras de Francisco |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine S-Adenosylmethionine Methyltransferase Antitubercular Agents Repressor Biology medicine.disease_cause Methylation Microbiology Mycobacterium tuberculosis 03 medical and health sciences Antibiotic resistance Bacterial Proteins Protein Domains Drug Resistance Bacterial medicine Tuberculosis Pathogen Antibacterial agent Mutation Multidisciplinary Molecular Structure Gene Expression Regulation Bacterial Methyltransferases biology.organism_classification Repressor Proteins 030104 developmental biology PNAS Plus Benzimidazoles |
| Popis: | Significance Better understanding of the mechanisms used by bacteria to counter antibacterial agents is essential to cope with the rising prevalence of antimicrobial resistance. Here, we identified the mechanism of resistance of Mycobacterium tuberculosis to an antimycobacterial cyano-substituted fused pyrido-benzimidazole. Clones bearing mutations in a transcription factor, Rv2887, markedly up-regulated the expression of rv0560c , a putative methyltransferase. Rv0560c N -methylated the pyrido-benzimidazole in vitro and in Mycobacterium tuberculosis , abrogating its bactericidal activity. Resistant mutants selected in the absence of rv0560c led to the identification of the target of the compound, the essential oxidoreductase, decaprenylphosphoryl-β- d -ribose 2-oxidase (DprE1). Methylation of an antibacterial compound is a previously uncharacterized mode of antimicrobial resistance. |
| Databáze: | OpenAIRE |
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