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Antimicrobial Agents and Chemotherapy, September 2005, p. 3847-3857, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3847-3857.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Structure-Function Characterization and Optimization of a Plant-Derived Antibacterial Peptide

Mougli Suarez,1 Marisa Haenni,2 Stéphane Canarelli,3 Florian Fisch,1 Pierre Chodanowski,4 Catherine Servis,5 Olivier Michielin,4 Ruth Freitag,3 Philippe Moreillon,2 and Nicolas Mermod1*

Institute of Biotechnology,1 Department of Fundamental Microbiology,2 Institute of Biochemistry, University of Lausanne, 1015 Lausanne, Switzerland,5 Laboratory of Chemical Biotechnology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland,3 Swiss Institute of Bioinformatics, 1066 Epalinges, Switzerland4

Received 25 May 2005/ Returned for modification 15 June 2005/ Accepted 23 June 2005

Crushed seeds of the Moringa oleifera tree have been used traditionally as natural flocculants to clarify drinking water. We previously showed that one of the seed peptides mediates both the sedimentation of suspended particles such as bacterial cells and a direct bactericidal activity, raising the possibility that the two activities might be related. In this study, the conformational modeling of the peptide was coupled to a functional analysis of synthetic derivatives. This indicated that partly overlapping structural determinants mediate the sedimentation and antibacterial activities. Sedimentation requires a positively charged, glutamine-rich portion of the peptide that aggregates bacterial cells. The bactericidal activity was localized to a sequence prone to form a helix-loop-helix structural motif. Amino acid substitution showed that the bactericidal activity requires hydrophobic proline residues within the protruding loop. Vital dye staining indicated that treatment with peptides containing this motif results in bacterial membrane damage. Assembly of multiple copies of this structural motif into a branched peptide enhanced antibacterial activity, since low concentrations effectively kill bacteria such as Pseudomonas aeruginosa and Streptococcus pyogenes without displaying a toxic effect on human red blood cells. This study thus identifies a synthetic peptide with potent antibacterial activity against specific human pathogens. It also suggests partly distinct molecular mechanisms for each activity. Sedimentation may result from coupled flocculation and coagulation effects, while the bactericidal activity would require bacterial membrane destabilization by a hydrophobic loop.

* Corresponding author. Mailing address: EPFL SB LBTM, CH B1 392, Station 6, CH 1015 Lausanne, Switzerland. Phone: 41 21 693 61 51. Fax: 41 21 693 76 10. E-mail: nicolas.mermod{at}unil.ch.

Antimicrobial Agents and Chemotherapy, September 2005, p. 3847-3857, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3847-3857.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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