A Pleurocidin Analogue with Greater Conformational Flexibility, Enhanced Antimicrobial Potency and in vivo Therapeutic Efficacy

Giorgia Manzo, Charlotte K. Hind, Philip Ferguson, Richard Amison, Alice Hodgson-Casson, Katarzyna Ciazynska, Bethany Weller, Maria Clarke, Carolyn Lam, Rico Man, Blaze O'Shaughnessy, Melanie Clifford, Tam Bui, Alexander Drake, Andrew Atkinson, Jenny Lam, Simon Pitchford, Clive Page, David Phoenix, Chris LorenzJ. Mark Sutton, James Mason

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
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Abstract

Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide-lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising D-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.
Original languageEnglish
Article number697
JournalCommunications Biology
Volume3
Issue number1
Early online date27 Nov 2020
DOIs
Publication statusPublished - 31 Dec 2020

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