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dc.contributor.authorLou, Hubing
dc.contributor.authorChen, Min
dc.contributor.authorBlack, Susan S.
dc.contributor.authorBushell, Simon R.
dc.contributor.authorCeccarelli, Matteo
dc.contributor.authorMach, Tivadar
dc.contributor.authorBeis, Konstantinos
dc.contributor.authorLow, Alison S.
dc.contributor.authorBamford, Victoria A.
dc.contributor.authorBooth, Ian R.
dc.contributor.authorBayley, Hagan
dc.contributor.authorNaismith, James H.
dc.date.accessioned2012-03-15T16:31:12Z
dc.date.available2012-03-15T16:31:12Z
dc.date.issued2011-10-28
dc.identifier.citationLou , H , Chen , M , Black , S S , Bushell , S R , Ceccarelli , M , Mach , T , Beis , K , Low , A S , Bamford , V A , Booth , I R , Bayley , H & Naismith , J H 2011 , ' Altered antibiotic transport in OmpC mutants isolated from a series of clinical strains of multi-drug resistant E. coli ' , PLoS One , vol. 6 , no. 10 , e25825 , pp. - . https://doi.org/10.1371/journal.pone.0025825en
dc.identifier.issn1932-6203
dc.identifier.otherPURE: 17448932
dc.identifier.otherPURE UUID: 11f3aec0-6492-4a48-8cda-67ce50bbc718
dc.identifier.otherWOS: 000299081800007
dc.identifier.otherScopus: 80055047308
dc.identifier.urihttps://hdl.handle.net/10023/2448
dc.descriptionThis work is also partially supported by BBSRC and the Scottish Funding Council (through SULSA)en
dc.description.abstractAntibiotic-resistant bacteria, particularly Gram negative species, present significant health care challenges. The permeation of antibiotics through the outer membrane is largely effected by the porin superfamily, changes in which contribute to antibiotic resistance. A series of antibiotic resistant E. coli isolates were obtained from a patient during serial treatment with various antibiotics. The sequence of OmpC changed at three positions during treatment giving rise to a total of four OmpC variants (denoted OmpC20, OmpC26, OmpC28 and OmpC33, in which OmpC20 was derived from the first clinical isolate). We demonstrate that expression of the OmpC K12 porin in the clinical isolates lowers the MIC, consistent with modified porin function contributing to drug resistance. By a range of assays we have established that the three mutations that occur between OmpC20 and OmpC33 modify transport of both small molecules and antibiotics across the outer membrane. This results in the modulation of resistance to antibiotics, particularly cefotaxime. Small ion unitary conductance measurements of the isolated porins do not show significant differences between isolates. Thus, resistance does not appear to arise from major changes in pore size. Crystal structures of all four OmpC clinical mutants and molecular dynamics simulations also show that the pore size is essentially unchanged. Molecular dynamics simulations suggest that perturbation of the transverse electrostatic field at the constriction zone reduces cefotaxime passage through the pore, consistent with laboratory and clinical data. This subtle modification of the transverse electric field is a very different source of resistance than occlusion of the pore or wholesale destruction of the transverse field and points to a new mechanism by which porins may modulate antibiotic passage through the outer membrane.
dc.format.extent15
dc.language.isoeng
dc.relation.ispartofPLoS Oneen
dc.rights© 2011 Lou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectQD Chemistryen
dc.subject.lccQDen
dc.titleAltered antibiotic transport in OmpC mutants isolated from a series of clinical strains of multi-drug resistant E. colien
dc.typeJournal articleen
dc.contributor.sponsorEuropean Commissionen
dc.contributor.sponsorThe Wellcome Trusten
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0025825
dc.description.statusPeer revieweden
dc.identifier.urlhttp://ukpmc.ac.uk/abstract/MED/22053181en
dc.identifier.grantnumberHEALTH-F3-2008-223461en
dc.identifier.grantnumber081862/Z/06/Zen


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