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J. Biol. Chem., Vol. 281, Issue 39, 28565-28574, September 29, 2006

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A Synergism between Temporins toward Gram-negative Bacteria Overcomes Resistance Imposed by the Lipopolysaccharide Protective Layer^*

Yosef Rosenfeld, Donatella Barra, Maurizio Simmaco, Yechiel Shai, and Maria Luisa Mangoni^¶1

From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel and the Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche and ^¶Unità di Diagnostica Molecolare Avanzata, II Facoltà di Medicina e Chirurgia, Università di Roma La Sapienza, Azienda Ospedaliera S. Andrea, 00189 Roma, Italy

Temporins are short and homologous antimicrobial peptides (AMPs) isolated from the frog skin of Rana genus. To date, very little is known about the biological significance of the presence of closely related AMPs in single living organisms. Here we addressed this question using temporins A, B, and L isolated from Rana temporaria. We found that temporins A and B are only weakly active toward Gram-negative bacteria. However, a marked synergism occurs when each is mixed with temporin L. To shed light on the underlying mechanisms involved in these activities, we used various experimental strategies to investigate: (i) the effect of the peptides' interaction on both the viability and membrane permeability of intact bacteria and spheroplasts; (ii) their interaction with lipopolysaccharides (LPS) and the effect of LPS on the oligomeric state of temporins, alone or combining one with another; (iii) their structure in solution and when bound to LPS, by using circular dichroism and ATR-FTIR spectroscopies. Our data reveal that temporin L synergizes with A and B by preventing their oligomerization in LPS. This should promote their translocation across the outer membrane into the cytoplasmic membrane. To the best of our knowledge, this is the first study that explains how a combination of native AMPs from the same species can overcome bacterial resistance imposed by the LPS leaflet.

Received for publication, June 23, 2006 , and in revised form, July 20, 2006.

^* This work was supported by the Italian Ministero dell'Università e della Ricerca Grant 2005062410 and by grants from the Università di Roma La Sapienza and Istituto di Biologia e Patologia Molecolari of the National Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Unità di Diagnostica Molecolare Avanzata, II Facoltà di Medicina e Chirurgia, Azienda Ospedaliera S. Andrea, Via di Grottarossa, 1035, 00189 Roma, Italy. Tel.: 39-06337-75457; Fax: 39-06337-75405; E-mail: marialuisa.mangoni{at}uniroma1.it.

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