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Article: A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy

TitleA pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy
Authors
Issue Date2020
PublisherNature Research: Fully open access journals. The Journal's web site is located at http://www.nature.com/commsbio
Citation
Communications Biology, 2020, v. 3, p. article no. 697 How to Cite?
AbstractAntimicrobial 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.
Persistent Identifierhttp://hdl.handle.net/10722/294651
ISSN
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorManzo, G-
dc.contributor.authorHind, CK-
dc.contributor.authorFerguson, PM-
dc.contributor.authorAmison, RT-
dc.contributor.authorHodgson-Casson, AC-
dc.contributor.authorCiazynska, KA-
dc.contributor.authorWeller, BJ-
dc.contributor.authorClarke, M-
dc.contributor.authorLam, C-
dc.contributor.authorMAN, RCH-
dc.contributor.authorShaughnessy, BGO-
dc.contributor.authorClifford, M-
dc.contributor.authorBui, TT-
dc.contributor.authorDrake, AF-
dc.contributor.authorAtkinson, RA-
dc.contributor.authorLam, JKW-
dc.contributor.authorPitchford, SC-
dc.contributor.authorPage, CP-
dc.contributor.authorPhoenix, DA-
dc.contributor.authorLorenz, CD-
dc.contributor.authorSutton, JM-
dc.contributor.authorMason, AJ-
dc.date.accessioned2020-12-08T07:39:59Z-
dc.date.available2020-12-08T07:39:59Z-
dc.date.issued2020-
dc.identifier.citationCommunications Biology, 2020, v. 3, p. article no. 697-
dc.identifier.issn2399-3642-
dc.identifier.urihttp://hdl.handle.net/10722/294651-
dc.description.abstractAntimicrobial 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.-
dc.languageeng-
dc.publisherNature Research: Fully open access journals. The Journal's web site is located at http://www.nature.com/commsbio-
dc.relation.ispartofCommunications Biology-
dc.rightsCommunications Biology. Copyright © Nature Research: Fully open access journals.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleA pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy-
dc.typeArticle-
dc.identifier.emailLam, JKW: jkwlam@hku.hk-
dc.identifier.authorityLam, JKW=rp01346-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s42003-020-01420-3-
dc.identifier.pmid33247193-
dc.identifier.pmcidPMC7699649-
dc.identifier.hkuros320419-
dc.identifier.volume3-
dc.identifier.spagearticle no. 697-
dc.identifier.epagearticle no. 697-
dc.identifier.isiWOS:000596316000001-
dc.publisher.placeUnited Kingdom-

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