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J. Biol. Chem., Vol. 279, Issue 27, 28233-28242, July 2, 2004

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Siderophore Peptide, a New Type of Post-translationally Modified Antibacterial Peptide with Potent Activity^*

Xavier Thomas, Delphine Destoumieux-Garzón, Jean Peduzzi, Carlos Afonso, Alain Blond, Nicolas Birlirakis¶, Christophe Goulard, Lionel Dubost, Robert Thai||, Jean-Claude Tabet, and Sylvie Rebuffat**

From the Laboratoire de Chimie et Biochimie des Substances Naturelles, UMR 5154 CNRS USM 502, the Département Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, 63 Rue Buffon, 75005 Paris, the Laboratoire de Chimie Structurale Organique et Biologique, UMR 7613 CNRS, Université Pierre et Marie Curie, 4 Place Jussieu, 75252 Paris Cedex 5, the ^¶CNRS, Laboratoire de RMN à Haut Champ, Institut de Chimie des Substances Naturelles, 91190 Gif-sur-Yvette, and the ^||Département d'Etude et d'Ingénierie des Protéines, CEA Saclay, 91190 Gif-sur-Yvette, France

Microcin E492 (MccE492, 7886 Da), the 84-amino acid antimicrobial peptide from Klebsiella pneumoniae, was purified in a post-translationally modified form, MccE492m (8717 Da), from culture supernatants of either the recombinant Escherichia coli VCS257 strain harboring the pJAM229 plasmid or the K. pneumoniae RYC492 strain. Chymotrypsin digestion of MccE492m led to the MccE492m-(74–84) C-terminal fragment that carries the modification and that was analyzed by mass spectrometry and nuclear magnetic resonance at natural abundance. The 831-Da post-translational modification consists of a trimer of N-(2,3-dihydroxybenzoyl)-L-serine linked via a C-glycosidic linkage to a -D-glucose moiety, itself linked to the MccE492m Ser-84-carboxyl through an O-glycosidic bond. This modification, which mimics a catechol-type siderophore, was shown to bind ferric ions by analysis of the collision-induced dissociation pattern obtained for MccE492m-(74–84) by electrospray ion trap mass spectrometry experiments in the presence of FeCl₃. By using a series of wild-type and mutant isogenic strains, the three catechol-type siderophore receptors Fiu, Cir, and FepA were shown to be responsible for the recognition of MccE492m at the outer membrane of sensitive bacteria. Because MccE492m shows a broader spectrum of antibacterial activity and is more potent than MccE492, we propose that by increasing the microcin/receptor affinity, the modification leads to a better recognition and subsequently to a higher antimicrobial activity of the microcin. Therefore, MccE492m is the first member of a new class of antimicrobial peptides carrying a siderophore-like post-translational modification and showing potent activity, which we term siderophore-peptides.

Received for publication, January 9, 2004 , and in revised form, April 19, 2004.

The abbreviations used are: DHBS, N-(2,3-dihydroxybenzoyl)-L-serine; ACN, acetonitrile; -D-Glc, -D-glucose; CID, collision-induced dissociation; ESI, electrospray ionization; HMBC, heteronuclear multiple bond correlation; HSQC, heteronuclear single quantum correlation; IT, ion trap; MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; Mcc, microcin; MIC, minimum inhibitory concentration; MS, mass spectrometry; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect spectroscopy; RP-HPLC, reversed phase high performance liquid chromatography; TOCSY, total correlation spectroscopy; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)]ethylglycine; Qq-TOF, hybrid quadrupole time-of-flight.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains Tables A and B.

^** To whom correspondence should be addressed. Tel.: 33-1-40-79-31-18; Fax: 33-1-40-79-31-35; E-mail: rebuffat{at}mnhn.fr.

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