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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Dependent Proteases / antagonists & inhibitors*
  • ATP-Dependent Proteases / metabolism
  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / isolation & purification
  • Anti-Bacterial Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Models, Molecular
  • Molecular Sequence Data
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / isolation & purification
  • Peptides, Cyclic / pharmacology*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / isolation & purification
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Peptides, Cyclic
  • Protease Inhibitors
  • lassomycin
  • ATP-Dependent Proteases

Associated data

  • PDB/2MAI