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Chem Biol. 2014 Apr 24;21(4):509-518. doi: 10.1016/j.chembiol.2014.01.014. Epub 2014 Mar 27.

Lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2.

Author information

1
Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
3
Goldberg Laboratory, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
4
NovoBiotic Pharmaceuticals, LLC, Cambridge, MA 02138, USA.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jon_clardy@hms.harvard.edu.
6
Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA. Electronic address: k.lewis@neu.edu.

Abstract

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.

PMID:
24684906
PMCID:
PMC4060151
DOI:
10.1016/j.chembiol.2014.01.014
[Indexed for MEDLINE]
Free PMC Article
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