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Antimicrob. Agents Chemother. doi:10.1128/AAC.00836-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Molecular mechanism of target recognition by subtilin, a class I lanthionine antibiotic

School of biomedical Sciences, University of Nottingham, Nottingham, UK; CBLE, Utrecht University, Padualaan 8, Utrecht, Holland; School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, NG7 2RD, UK; BBSRC Institute for Food Research, Norwich, UK

^* To whom correspondence should be addressed. Email: Boyan.Bonev{at}nottingham.ac.uk.

	Abstract

Increasing resistance of human pathogens to conventional antibiotics presents a growing threat to the chemotherapeutic management of infectious diseases. The class of lanthionine antibiotics, still unused as therapeutic agents, have attracted recently significant scientific interest as models for targeting and management of bacterial infections. We investigated the action of one member of this class, subtilin, which permeabilises lipid membranes in a lipid II-dependent manner and binds bactoprenyl pyrophosphate, akin to nisin. The role the C- and N-termini play in target recognition was investigated in vivo and in vitro using the natural N-terminally succinylated subtilin, as well as enzymatically truncated subtilin variants. Fluorescence de-quenching experiments show that subtilin induces leakage in membranes in a lipid II-dependant manner and that N-succinylated subtilin is roughly 75-fold less active. Solid state NMR was used to show that subtilin forms complexes with membrane isoprenyl pyrophosphates. Activity assays in vivo show that the N-terminus of subtilin plays a critical in its activity. Succinylation of the N-terminus resulted in a 20-fold decrease in its activity, while deletion of N-terminal Trp abolished activity altogether.

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