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dc.contributor.authorCollins, S. A.
dc.contributor.authorKelso, M. J.
dc.contributor.authorRineh, A.
dc.contributor.authorYepuri, N. R.
dc.contributor.authorColes, J.
dc.contributor.authorJackson, C. L.
dc.contributor.authorHalladay, G. D.
dc.contributor.authorWalker, W. T.
dc.contributor.authorWebb, J. S.
dc.contributor.authorHall-Stoodley, L.
dc.contributor.authorConnett, G.
dc.contributor.authorFeelisch, M.
dc.contributor.authorFaust, S. N.
dc.contributor.authorLucas, J. S. A.
dc.contributor.authorAllan, Raymond N.
dc.date.accessioned2019-09-02T09:58:01Z
dc.date.available2019-09-02T09:58:01Z
dc.date.issued2016-12-05
dc.identifier.citationCollins, S.A. et al. (2017) Cephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D enhances azithromycin susceptibility of non-typeable Haemophilus influenzae biofilms. Antimicrobial Agents and Chemotherapy, 61 (2), e02086-16en
dc.identifier.urihttps://www.dora.dmu.ac.uk/handle/2086/18384
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.abstractObjectives: PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO)-donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against non-typeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. Methods: The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free LC/MS proteomic analyses were performed to identify differentially expressed proteins following NO treatment. Results: PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking β-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log-fold reduction in viability (p<0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log reduction was observed (p<0.01). Label-free proteomics showed that NO increased expression of sixteen proteins involved in metabolic and transcriptional/translational functions. Conclusions: NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm associated antibiotic tolerance.en
dc.language.isoenen
dc.publisherAmerican Society for Microbiologyen
dc.subjectHaemophilus influenzaeen
dc.subjectNitric oxideen
dc.subjectBiofilmen
dc.subjectAntimicrobialen
dc.titleCephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D enhances azithromycin susceptibility of non-typeable Haemophilus influenzae biofilmsen
dc.typeArticleen
dc.identifier.doihttps://doi.org/10.1128/aac.02086-16
dc.peerreviewedYesen
dc.funderNo external funderen
dc.cclicenceCC-BY-NC-NDen
dc.date.acceptance2016-11-26
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en
dc.exception.ref2021codes254aen


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