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Subinhibitory concentrations of the deformylase inhibitor actinonin increase bacterial release of neutrophil-activating peptides: a new approach to antimicrobial chemotherapy

Journal article
Authors Huamei Fu
Claes Dahlgren
Johan Bylund
Published in Antimicrob Agents Chemother
Volume 47
Issue 8
Pages 2545-50
Publication year 2003
Published at Institute of Internal Medicine, Dept of Rheumatology and Inflammation Research
Pages 2545-50
Language en
Keywords *Amidohydrolases, Aminopeptidases/*antagonists & inhibitors, Anti-Bacterial Agents/*pharmacology, Bacteria/drug effects/*metabolism, Chemotactic Factors/metabolism, Chemotaxis, Leukocyte/drug effects, Enzyme Inhibitors/*pharmacology, Escherichia coli/drug effects/metabolism, Escherichia coli Infections/microbiology, Humans, Hydroxamic Acids/*pharmacology, Interleukin-8/*metabolism, NADPH Oxidase/metabolism, Neutrophils/drug effects/metabolism
Subject categories Medical and Health Sciences


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.

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