Targeting extracellular pyrophosphates underpins the high selectivity of nisin.

Journal article

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: Bonev, B; Breukink, E; Swiezewska, E; De Kruijff, B; Watts, A

• Publication status: Published
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• Volume: 18
• Issue: 15
• Pages: 1862-1869
• Publication date: 2004-12-01
• DOI: 10.1096/fj.04-2358com
• EISSN: 1530-6860
• ISSN: 0892-6638
• Language: English
• Keywords: Polyisoprenyl Phosphates; Cell Wall; Diphosphates; Lipid Bilayers; Nisin; Uridine Diphosphate N-Acetylmuramic Acid; Magnetic Resonance Spectroscopy; Amino Acid Sequence; Molecular Sequence Data; Binding Sites; Anti-Bacterial Agents; Peptidoglycan