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Antimicrobial Agents and Chemotherapy, August 2003, p. 2545-2550, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2545-2550.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Subinhibitory Concentrations of the Deformylase Inhibitor Actinonin Increase Bacterial Release of Neutrophil-Activating Peptides: a New Approach to Antimicrobial Chemotherapy

Huamei Fu,1* Claes Dahlgren,1 and Johan Bylund2

The Phagocyte Research Laboratory, Department for Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden,1 British Columbia Research Institute for Children's and Women's Health, Vancouver, British Columbia V5Z 4H4, Canada2

Received 2 December 2002/ Returned for modification 10 March 2003/ Accepted 24 May 2003

Bacterial protein synthesis starts with a formylated methionine residue, and this residue is sequentially cleaved away by a unique peptide deformylase (PDF) and a methionine aminopeptidase to generate mature proteins. The formylation-deformylation of proteins is a unique hallmark of bacterial metabolism and has recently become an attractive target for the development of antimicrobial agents. The innate immune system uses the formylation of bacterial proteins as a target, and professional phagocytes, e.g., neutrophils, express specific receptors for bacterium-derived formylated peptides. Activation of formyl peptide receptors (FPR) mediates neutrophil migration and the release of oxygen radicals and other antimicrobial substances from these cells. We hypothesize that the use of a PDF inhibitor would increase the production of proinflammatory peptides from the bacteria and thus trigger a more pronounced innate immune response. We tested this hypothesis by exposing Escherichia coli to subinhibitory doses of the PDF inhibitor actinonin and show that actinonin indeed increases the production and secretion of neutrophil-activating peptides that activate human neutrophils through FPR. These findings could be potentially used as a new approach to antibacterial chemotherapy.

* Corresponding author. Mailing address: Department of Rheumatology and Inflammation Research, University of Göteborg, Guldhedsgatan 10, 413 46 Göteborg, Sweden. Phone: 46-313424635. Fax: 46-31828898. E-mail: Huamei.Fu{at}microbio.gu.se.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2545-2550, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2545-2550.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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