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Antimicrobial Agents and Chemotherapy, October 2006, p. 3305-3311, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00490-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Enhanced Membrane Disruption and Antibiotic Action against Pathogenic Bacteria by Designed Histidine-Rich Peptides at Acidic pH

A. James Mason,*1 Claire Gasnier,2 Antoine Kichler,3 Gilles Prévost,4 Dominique Aunis,2 Marie-Hélène Metz-Boutigue,2 and Burkhard Bechinger1

Faculté de Chimie, University Louis Pasteur/CNRS LC3-UMR7177, Institut le Bel, 4 rue Blaise Pascal, F-67070 Strasbourg, France,1 INSERM Unité 575, Physiopathologie du Système Nerveux, 5 rue Blaise Pascal, F-67084 Strasbourg, France,2 Généthon-CNRS UMR8115, 1 rue de l'Internationale, BP60, F-91002 Evry, France,3 UPRES EA-3432 Institut de Bactériologie ULP-HUS, 3 rue Koeberlé, F-67000 Strasbourg, France4

Received 20 April 2006/ Returned for modification 9 June 2006/ Accepted 14 July 2006

The histidine-rich amphipathic cationic peptide LAH4 has antibiotic and DNA delivery capabilities. Here, we explore the interaction of peptides from this family with model membranes as monitored by solid-state 2H nuclear magnetic resonance and their antibiotic activities against a range of bacteria. At neutral pH, the membrane disruption is weak, but at acidic pH, the peptides strongly disturb the anionic lipid component of bacterial membranes and cause bacterial lysis. The peptides are effective antibiotics at both pH 7.2 and pH 5.5, although the antibacterial activity is strongly affected by the change in pH. At neutral pH, the LAH peptides were active against both methicillin-resistant and -sensitive Staphylococcus aureus strains but ineffective against Pseudomonas aeruginosa. In contrast, the LAH peptides were highly active against P. aeruginosa in an acidic environment, as is found in the epithelial-lining fluid of cystic fibrosis patients. Our results show that modest antibiotic activity of histidine-rich peptides can be dramatically enhanced by inducing membrane disruption, in this case by lowering the pH, and that histidine-rich peptides have potential as future antibiotic agents.

* Corresponding author. Present address: Institut Isis, 8 rue Gaspard Monge, 67083 Strasbourg, France. Phone: 33 3 90 24 51 52. Fax: 33 3 90 24 51 51. E-mail: jmason{at}chimie.u-strasbg.fr.

Antimicrobial Agents and Chemotherapy, October 2006, p. 3305-3311, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00490-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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