Mycolic acid cyclopropanation is essential for viability, drug resistance, and cell wall integrity of mycobacterium tuberculosis Journal Article
| Authors: | Barkan, D.; Liu, Z.; Sacchettini, J. C.; Glickman, M. S. |
| Article Title: | Mycolic acid cyclopropanation is essential for viability, drug resistance, and cell wall integrity of mycobacterium tuberculosis |
| Abstract: | Mycobacterium tuberculosis infection remains a major global health problem complicated by escalating rates of antibiotic resistance. Despite the established role of mycolic acid cyclopropane modification in pathogenesis, the feasibility of targeting this enzyme family for antibiotic development is unknown. We show through genetics and chemical biology that mycolic acid methyltransferases are essential for M. tuberculosis viability, cell wall structure, and intrinsic resistance to antibiotics. The tool compound dioctylamine, which we show acts as a substrate mimic, directly inhibits the function of multiple mycolic acid methyltransferases, resulting in loss of cyclopropanation, cell death, loss of acid fastness, and synergistic killing with isoniazid and ciprofloxacin. These results demonstrate that mycolic acid methyltransferases are a promising antibiotic target and that a family of virulence factors can be chemically inhibited with effects not anticipated from studies of each individual enzyme. © 2009 Elsevier Ltd. All rights reserved. |
| Keywords: | genetics; phenotype; metabolism; drug effect; enzymology; structure activity relation; structure-activity relationship; growth, development and aging; chembio; microbio; amine; antiinfective agent; bacterial protein; cmaa2 protein, mycobacterium tuberculosis; cyclopropane derivative; methyltransferase; mycolic acid; octylamine; antibiotic resistance; cell wall; chemistry; drug antagonism; mycobacterium tuberculosis; amines; anti-bacterial agents; bacterial proteins; cyclopropanes; drug resistance, bacterial; methyltransferases; mycolic acids |
| Journal Title: | Chemistry and Biology |
| Volume: | 16 |
| Issue: | 5 |
| ISSN: | 1074-5521 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2009-05-29 |
| Start Page: | 499 |
| End Page: | 509 |
| Language: | English |
| DOI: | 10.1016/j.chembiol.2009.04.001 |
| PUBMED: | 19477414 |
| PROVIDER: | scopus |
| PMCID: | PMC2731493 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 7" - "Export Date: 30 November 2010" - "CODEN: CBOLE" - "Source: Scopus" |
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