title: Lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2.
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.
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Gavrish
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Clarissa S
authors.initials: CS
authors.lastname: Sit
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shugeng
authors.initials: S
authors.lastname: Cao
authors.affiliation: Goldberg Laboratory, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Kandror
authors.affiliation: NovoBiotic Pharmaceuticals, LLC, Cambridge, MA 02138, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Spoering
authors.affiliation: NovoBiotic Pharmaceuticals, LLC, Cambridge, MA 02138, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Peoples
authors.affiliation: NovoBiotic Pharmaceuticals, LLC, Cambridge, MA 02138, USA.
authors.forename: Losee
authors.initials: L
authors.lastname: Ling
authors.affiliation: NovoBiotic Pharmaceuticals, LLC, Cambridge, MA 02138, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Fetterman
authors.affiliation: NovoBiotic Pharmaceuticals, LLC, Cambridge, MA 02138, USA.
authors.forename: Dallas
authors.initials: D
authors.lastname: Hughes
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Bissell
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Torrey
authors.affiliation: Goldberg Laboratory, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tatos
authors.initials: T
authors.lastname: Akopian
authors.affiliation: Goldberg Laboratory, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mueller
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Slava
authors.initials: S
authors.lastname: Epstein
authors.affiliation: Goldberg Laboratory, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Goldberg
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jon_clardy@hms.harvard.edu.
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA. Electronic address: k.lewis@neu.edu.
authors.forename: Kim
authors.initials: K
authors.lastname: Lewis
mesh_terms: D049069:ATP-Dependent Proteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; C000595674:lassomycin; D049069:ATP-Dependent Proteases