title: Total Synthesis of Laspartomycin C and Characterization of Its Antibacterial Mechanism of Action.
abstract: Laspartomycin C is a lipopeptide antibiotic with activity against a range of Gram-positive bacteria including drug-resistant pathogens. We report the first total synthesis of laspartomycin C as well as a series of structural variants. Laspartomycin C was found to specifically bind undecaprenyl phosphate (C55-P) and inhibit formation of the bacterial cell wall precursor lipid II. While several clinically used antibiotics target the lipid II pathway, there are no approved drugs that act on its C55-P precursor.
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Laurens H J
authors.initials: LH
authors.lastname: Kleijn
authors.affiliation: Membrane Biochemistry and Biophysics Group, Department of Chemistry, Utrecht University , Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Sabine F
authors.initials: SF
authors.lastname: Oppedijk
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: 't Hart
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Roel M
authors.initials: RM
authors.lastname: van Harten
authors.affiliation: The King's University , 9125 50th Street, Edmonton, Alberta T6B 2H3, Canada.
authors.forename: Leah A
authors.initials: LA
authors.lastname: Martin-Visscher
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kemmink
authors.affiliation: Membrane Biochemistry and Biophysics Group, Department of Chemistry, Utrecht University , Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Nathaniel I
authors.initials: NI
authors.lastname: Martin
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects*; D055666:Lipopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D055666:Lipopeptides; D010456:Peptides, Cyclic; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C519250:laspartomycin C; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol