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Antimicrobial Agents and Chemotherapy, April 2006, p. 1251-1256, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1251-1256.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Activity of Cecropin A-Melittin Hybrid Peptides against Colistin-Resistant Clinical Strains of Acinetobacter baumannii: Molecular Basis for the Differential Mechanisms of Action

Centro de Investigaciones Biológicas (CSIC), C/Ramiro de Maeztu 9, 28040 Madrid,¹ Services of Infectious Diseases,² Emergency and Critical Care, Hospitales Universitarios Virgen del Rocío, Avda. Manuel Siurot s/n, 41013 Sevilla,³ Department of Experimental and Health Sciences, Pompeu Fabra University, Dr Aiguader 80, 08003 Barcelona, Spain⁴

Received 31 October 2005/ Returned for modification 13 December 2005/ Accepted 31 January 2006

Acinetobacter baumannii has successfully developed resistance against all common antibiotics, including colistin (polymyxin E), the last universally active drug against this pathogen. The possible widespread distribution of colistin-resistant A. baumannii strains may create an alarming clinical situation. In a previous work, we reported differences in lethal mechanisms between polymyxin B (PXB) and the cecropin A-melittin (CA-M) hybrid peptide CA(1-8)M(1-18) (KWKLFKKIGIGAVLKVLTTGLPALIS-NH₂) on colistin-susceptible strains (J. M. Saugar, T. Alarcón, S. López-Hernández, M. López-Brea, D. Andreu, and L. Rivas, Antimicrob. Agents Chemother. 46:875-878, 2002). We now demonstrate that CA(1-8)M(1-18) and three short analogues, namely CA(1-7)M(2-9) (KWKLFKKIGAVLKVL-NH₂), its N-octanoyl derivative (Oct-KWKLFKKIGAVLKVL-NH₂), and CA(1-7)M(5-9) (KWKLLKKIGAVLKVL-NH₂) are active against two colistin-resistant clinical strains. In vitro, resistance to colistin sulfate was targeted to the outer membrane, as spheroplasts were equally lysed by a given peptide, regardless of their respective level of colistin resistance. The CA-M hybrids were more efficient than colistin in displacing lipopolysaccharide-bound dansyl-polymyxin B from colistin-resistant but not from colistin-susceptible strains. Similar improved performance of the CA-M hybrids in permeation of the inner membrane was observed, regardless of the resistance pattern of the strain. These results argue in favor of a possible use of CA-M peptides, and by extension other antimicrobial peptides with similar features, as alternative chemotherapy in colistin-resistant Acinetobacter infections.

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• Peleg, A. Y., Seifert, H., Paterson, D. L. (2008). Acinetobacter baumannii: Emergence of a Successful Pathogen. Clin. Microbiol. Rev. 21: 538-582 [Abstract] [Full Text]  
• Bastos, M., Bai, G., Gomes, P., Andreu, D., Goormaghtigh, E., Prieto, M. (2008). Energetics and Partition of Two Cecropin-Melittin Hybrid Peptides to Model Membranes of Different Composition. Biophys. J 94: 2128-2141 [Abstract] [Full Text]