Journal
CHEMISTRY & BIOLOGY
Volume 16, Issue 5, Pages 499-509Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2009.04.001
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Funding
- Michael and Ethel L. Cohen Foundation
- National Institutes of Health (NIH) [T32 AI055409, AI53417, P01AI068135]
- Robert A. Welch Foundation
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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 anticipate from studies of each individual enzyme.
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