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Antimicrobial Agents and Chemotherapy, February 2008, p. 483-490, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00585-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Pre-Elafin Inhibits a Pseudomonas aeruginosa-Secreted Peptidase and Prevents Its Proliferation in Complex Media

Audrey Bellemare, Nathalie Vernoux, Dany Morisset, and Yves Bourbonnais^*

Département de Biochimie et de Microbiologie and Centre de Recherche sur la Fonction, la Structure et l'Ingénierie des Protéines, Université Laval, Québec, Quebec G1K 7P4, Canada

Received 3 May 2007/ Returned for modification 3 July 2007/ Accepted 31 October 2007

Pseudomonas aeruginosa is a life-threatening opportunist human pathogen frequently associated with lung inflammatory diseases, namely, cystic fibrosis. Like other species, this gram-negative bacteria is increasingly drug resistant. During the past decade, intensive research efforts have been focused on the identification of natural innate defense molecules with broad antimicrobial activities, collectively known as antimicrobial peptides. Human pre-elafin, best characterized as a potent inhibitor of neutrophil elastase with anti-inflammatory properties, was also shown to possess antimicrobial activity against both gram-positive and gram-negative bacteria, including P. aeruginosa. Its mode of action was, however, not known. Using full-length pre-elafin, each domain separately, and mutated variants of pre-elafin with attenuated antipeptidase activity toward neutrophil elastase, we report here that both pre-elafin domains contribute, through distinct mechanisms, to its antibacterial activity against Pseudomonas aeruginosa. Most importantly, we demonstrate that the whey acidic protein (WAP) domain specifically inhibits a secreted peptidase with the characteristics of arginyl peptidase (protease IV). This is the first demonstration that a human WAP-motif protein inhibits a secreted peptidase to prevent bacterial growth in vitro. Since several WAP-motif proteins from various species demonstrate antimicrobial function with variable activities toward bacterial species, we suggest that this mechanism may be more common than initially anticipated.

Published ahead of print on 19 November 2007.

Present address: Department of Biotechnology and Systems Biology, National Institute of Biology, Vecna pot 111, Ljubljana, Slovenia.