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Antimicrobial Agents and Chemotherapy, September 2001, p. 2441-2449, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2441-2449.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

N-Terminal Fatty Acid Substitution Increases the Leishmanicidal Activity of CA(1-7)M(2-9), a Cecropin-Melittin Hybrid Peptide

Cristina Chicharro,1 Cesare Granata,2,dagger Rosario Lozano,1 David Andreu,2 and Luis Rivas1,*

Centro de Investigaciones Biológicas (CSIC), Velázquez 144, 28006 Madrid,1 and Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona,2 Spain

Received 16 February 2001/Returned for modification 18 April 2001/Accepted 5 June 2001

In order to improve the leishmanicidal activity of the synthetic cecropin A-melittin hybrid peptide CA(1-7)M(2-9) (KWKLFKKIGAVLKVL-NH2), a systematic study of its acylation with saturated linear fatty acids was carried out. Acylation of the Nepsilon -7 lysine residue led to a drastic decrease in leishmanicidal activity, whereas acylation at lysine 1, in either the alpha  or the varepsilon  NH2 group, increased up to 3 times the activity of the peptide against promastigotes and increased up to 15 times the activity of the peptide against amastigotes. Leishmanicidal activity increased with the length of the fatty acid chain, reaching a maximum for the lauroyl analogue (12 carbons). According to the fast kinetics, dissipation of membrane potential, and parasite membrane permeability to the nucleic acid binding probe SYTOX green, the lethal mechanism was directly related to plasma membrane permeabilization.

* Corresponding author. Mailing address: Centro de Investigaciones Biológicas, Velázquez 144, E-28006, Madrid, Spain. Phone: 34 915 611 800, ext. 4234. Fax: 34 915 627 518. E-mail: luis_rivas{at}cib.csic.es.

dagger Present address: Roche Discovery, Welwyn, Hertfordshire, United Kingdom.

Antimicrobial Agents and Chemotherapy, September 2001, p. 2441-2449, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2441-2449.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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