Abstract
The Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a polycationic, amphiphilic and helical neuropeptide, is well known for its neuroprotective actions and cell penetrating properties. In the present study, we evaluated the potent antibacterial property of PACAP38 and related analogs against various bacterial strains. Interestingly, PACAP38 and related analogs can inhibit the growth of various bacteria including Escherichia coli (JM109), Bacillus subtilis (PY79), and the pathogenic Burkholderia cenocepacia (J2315). Investigation of the mechanism of action suggested that a PACAP metabolite, identified as PACAP(9–38), might indeed be responsible for the observed PACAP38 antibacterial action. Surprisingly, PACAP(9–38), which does not induce haemolysis, exhibits an increased specificity toward Burkholderia cenocepacia J2315 compared to other tested bacteria. Finally, the predisposition of PACAP(9–38) to adopt a π-helix conformation rather than an α-helical conformation like PACAP38 could explain this gain in specificity. Overall, this study has revealed a new function for PACAP38 and related derivatives that can be added to its pleiotropic biological activities. This innovative study could therefore pave the way toward the development of new therapeutic agents against multiresistant bacteria, and more specifically the Burkholderia cenocepacia complex.
Highlights
Increased bacterial resistance to available antibiotics is a situation of global concern[1]
Our results demonstrate the potent antibacterial activity of 38-amino acid isoform of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) (PACAP38) against various bacterial strains, helping us identify a lead template, i.e. PACAP(9–38), that appears to be specific against Burkholderia cenocepacia, an epidemic pathogen of cystic fibrosis patients
The physico-chemical characteristics of PACAP38, i.e. extended α-helix containing 11 basic residues[8], as well as its cell-penetrating properties(10), a characteristic often associated with antimicrobial activity, prompted us to evaluate the propensity of PACAP to exert antibacterial activity
Summary
Increased bacterial resistance to available antibiotics is a situation of global concern[1] Based on their broad spectrum of activities and usually non-immunogenic action, antimicrobial peptides (AMPs) isolated from various species including plants, mammals, insects, and marine invertebrates[2], represent promising alternatives to traditional antibiotics. Natural antimicrobial peptides are relatively short polypeptides (fewer than 60 amino acid residues) that generally possess a positive net charge and amphipathic properties upon interaction with membranes[3]. Based on their structural (linear or helical) and biochemical properties N.D. holds a Fonds de Recherche Quebec – Sante (FRQS) Research Scholar Junior 2 Career Award
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