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Antimicrobial Agents and Chemotherapy, February 2008, p. 612-618, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00836-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Molecular Mechanism of Target Recognition by Subtilin, a Class I Lanthionine Antibiotic{triangledown}

Judicaël Parisot,1 Sarah Carey,1 Eefjan Breukink,2 Weng C. Chan,3 Arjan Narbad,4 and Boyan Bonev1*

School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom,1 CBLE, Utrecht University, Padualaan 8, Utrecht, Holland,2 School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom,3 BBSRC Institute for Food Research, Norwich, United Kingdom4

Received 27 June 2007/ Returned for modification 31 July 2007/ Accepted 31 October 2007

The increasing resistance of human pathogens to conventional antibiotics presents a growing threat to the chemotherapeutic management of infectious diseases. The lanthionine antibiotics, still unused as therapeutic agents, have recently attracted significant scientific interest as models for targeting and management of bacterial infections. We investigated the action of one member of this class, subtilin, which permeabilizes 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 by using the natural N-terminally succinylated subtilin as well as enzymatically truncated subtilin variants. Fluorescence dequenching experiments show that subtilin induces leakage in membranes in a lipid II-dependent manner and that N-succinylated subtilin is roughly 75-fold less active. Solid-state nuclear magnetic resonance 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 role in its activity. Succinylation of the N terminus resulted in a 20-fold decrease in its activity, whereas deletion of N-terminal Trp abolished activity altogether.

* Corresponding author. Mailing address: School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom. Phone: 44 (0)115 823 0177. Fax: 44 (0) 115 823 0142. E-mail: Boyan.Bonev{at}nottingham.ac.uk

{triangledown} Published ahead of print on 12 November 2007.

Antimicrobial Agents and Chemotherapy, February 2008, p. 612-618, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00836-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bottiger, T., Schneider, T., Martinez, B., Sahl, H.-G., Wiedemann, I. (2009). Influence of Ca2+ Ions on the Activity of Lantibiotics Containing a Mersacidin-Like Lipid II Binding Motif. Appl. Environ. Microbiol. 75: 4427-4434 [Abstract] [Full Text]  
  • Bonev, B., Hooper, J., Parisot, J. (2008). Principles of assessing bacterial susceptibility to antibiotics using the agar diffusion method. J Antimicrob Chemother 61: 1295-1301 [Abstract] [Full Text]  


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