期刊
CHEMISTRY & BIOLOGY
卷 21, 期 4, 页码 509-518出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2014.01.014
关键词
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资金
- NIH (National Institute of Allergy and Infectious Disease) [SBIR43/44 A1091224-03]
- National Institute of General Medical Sciences [2R01GM051923-17A1]
- Hoffmann-La Roche
- NIH [R01 GM086258, Al U54 A1057159]
- Alberta Innovates Health Solutions full-time fellowship
- Natural Sciences and Engineering Research Council of Canada Banting fellowship
- [R01 A1076372]
- [T-R01A1085585]
Languishing antibiotic discovery and flourishing antibiotic resistance have prompted the development of alternative untapped sources for antibiotic discovery, including previously uncultured bacteria. Here, we screen extracts from uncultured species against Mycobacterium tuberculosis and identify lassomycin, an antibiotic that exhibits potent bactericidal activity against both growing and dormant mycobacteria, including drug-resistant forms of M. tuberculosis, but little activity against other bacteria or mammalian cells. Lassomycin is a highly basic, ribosomally encoded cyclic peptide with an unusual structural fold that only partially resembles that of other lasso peptides. We show that lassomycin binds to a highly acidic region of the ClpC1 ATPase complex and markedly stimulates its ATPase activity without stimulating ClpP1P2-catalyzed protein breakdown, which is essential for viability of mycobacteria. This mechanism, uncoupling ATPase from proteolytic activity, accounts for the bactericidal activity of lassomycin.
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