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dc.contributor.authorAllan, Raymond N.
dc.contributor.authorKelso, M.J.
dc.contributor.authorRineh, A.
dc.contributor.authorYepuri, N.R.
dc.contributor.authorFeelisch, M.
dc.contributor.authorSoren, O.
dc.contributor.authorBrito-Mutunayagam, S.
dc.contributor.authorSalib, R.J.
dc.contributor.authorStoodley, P.
dc.contributor.authorClarke, S.C.
dc.contributor.authorWebb, J.S.
dc.contributor.authorHall-Stoodley, L.
dc.contributor.authorFaust, S.N.
dc.date.accessioned2019-09-04T08:52:05Z
dc.date.available2019-09-04T08:52:05Z
dc.date.issued2017-02-21
dc.identifier.citationAllan, R.N., Kelso, M.J., Rineh, A., Yepuri, N.R., Feelisch, M., Soren, O., Brito-Mutunayagam, S., Salib, R.J., Stoodley, P., Clarke, S.C., Webb, J.S., Hall-Stoodley, L., Faust, S.N. (2017) Cephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D is active against Streptococcus pneumoniae biofilms despite the absence of -lactamases. Nitric Oxide, 65, pp. 43-45.en
dc.identifier.issn1089-8603
dc.identifier.urihttps://www.dora.dmu.ac.uk/handle/2086/18391
dc.descriptionThe file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.en
dc.description.abstractBacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings where they are a primary cause of chronic infections. Novel therapeutic strategies are needed to improve anti-biofilm efficacy and support reduction in antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that render biofilms more susceptible to antibiotics.We previously reported on cephalosporin-3’-diazeniumdiolates (C3Ds) as NO-donor prodrugs designed to selectively deliver NO to bacterial infection sites following reaction with b-lactamases. With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO following b-lactam cleavage mediated by transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (b-lactam-mediated) antibacterial effects. This dual-activity concept was explored using Streptococcus pneumoniae, a species that lacks b-lactamases but relies on transpeptidases for cell-wall synthesis. Treatment with PYRRO-C3D (a representative C3D containing the diazeniumdiolate NO donor PYRRO-NO) was found to significantly reduce viability of planktonic and biofilm pneumococci, demonstrating that C3Ds can elicit direct, cephalosporin-like antibacterial activity in the absence of b-lactamases. While NO release from PYRRO-C3D in the presence of pneumococci was confirmed, the anti-pneumococcal action of the compound was shown to arise exclusively from the b-lactam component and not through NO-mediated effects. The compound showed similar potency to amoxicillin against S. pneumoniae biofilms and greater efficacy than azithromycin, highlighting the potential of C3Ds as new agents for treating pneumococcal infections.en
dc.language.isoenen
dc.publisherElsevieren
dc.subjectNitric oxideen
dc.subjectStreptococcus pneumoniaeen
dc.subjectBiofilmen
dc.titleCephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D is active against Streptococcus pneumoniae biofilms despite the absence of -lactamasesen
dc.typeArticleen
dc.identifier.doihttps://doi.org/10.1016/j.niox.2017.02.006
dc.peerreviewedYesen
dc.funderOther external funder (please detail below)en
dc.projectid11STH01en
dc.cclicenceCC-BY-NC-NDen
dc.date.acceptance2017-02-16
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en
dc.exception.ref2021codes254aen
dc.funder.otherSparks Children's Medical Research Charityen


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