title: Targeting extracellular pyrophosphates underpins the high selectivity of nisin.
abstract: The spread of infectious diseases and the increase in antibiotic resistance represent a life-threatening global development that calls for new approaches to control microorganisms. Of all potential targets, the essential and unique pathway of bacterial cell wall synthesis, targeted by the first known antibiotic penicillin, remains a perfect candidate for the development of new antibiotics. Here we show that the lantibiotic nisin exercises its antibacterial action by targeting peptidoglycan intermediates' extracellular pyrophosphate, unique to bacterial cell wall precursors. We show that nisin sequesters cell wall precursors found in the outer leaflet of bacterial plasma membranes, Lipid II and undecaprenyl pyrophosphate, into stable complexes. We propose a model of antibacterial action for nisin in which the terminal amino group of Ile1 targets the pyrophosphate groups of the bacterial cell wall precursors, where it docks via a hydrogen bond. The pyrophosphate moiety, a highly conserved chemical group different from the L-Lys-D-Ala-D-Ala docking motif for vancomycin, has no biochemical analogs with comparable properties and is unlikely to be susceptible to bacterial adaptations akin to those responsible for resistance to penicillins and vancomycin.
authors.affiliation: Biomembrane Structure Unit, Department of Biochemistry, University of Oxford, Oxford, UK. Boyan.Bonev@nottingham.ac.uk
authors.forename: Boyan B
authors.initials: BB
authors.lastname: Bonev
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.forename: E
authors.initials: E
authors.lastname: Swiezewska
authors.forename: Ben
authors.initials: B
authors.lastname: De Kruijff
authors.forename: Anthony
authors.initials: A
authors.lastname: Watts
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D011756:Diphosphates / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009561:Nisin / Q000737:chemistry / Q000494:pharmacology*; D010457:Peptidoglycan / Q000096:biosynthesis; D011106:Polyisoprenyl Phosphates / Q000737:chemistry* / Q000378:metabolism; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D011756:Diphosphates; D008051:Lipid Bilayers; D010457:Peptidoglycan; D011106:Polyisoprenyl Phosphates; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D009561:Nisin; C088139:undecaprenyl pyrophosphate