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dc.contributor.authorLuscher, Alexandre
dc.contributor.authorMoynie, Lucile
dc.contributor.authorAuguste, Pamela Saint
dc.contributor.authorBumann, Dirk
dc.contributor.authorMazza, Lena
dc.contributor.authorPletzer, Daniel
dc.contributor.authorNaismith, James H.
dc.contributor.authorKöhlera, Thilo
dc.date.accessioned2018-06-07T11:30:07Z
dc.date.available2018-06-07T11:30:07Z
dc.date.issued2018-06
dc.identifier253302721
dc.identifier3e8012c9-078c-481b-819d-f2eba60fa3ac
dc.identifier85047450608
dc.identifier000433240200004
dc.identifier.citationLuscher , A , Moynie , L , Auguste , P S , Bumann , D , Mazza , L , Pletzer , D , Naismith , J H & Köhlera , T 2018 , ' TonB-dependent receptor repertoire of pseudomonas aeruginosa for uptake of siderophore-drug conjugates ' , Antimicrobial Agents and Chemotherapy , vol. 62 , no. 6 , e00097-18 . https://doi.org/10.1128/AAC.00097-18en
dc.identifier.issn0066-4804
dc.identifier.urihttps://hdl.handle.net/10023/13812
dc.descriptionThe research leading to these results was conducted as part of the Translocation consortium (www.translocation.eu) and has received support from the Innovative Medicines Joint Undertaking under grant agreement no. 115525, resources which are composed of financial contribution from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies in kind contribution.en
dc.description.abstractThe conjugation of siderophores to antimicrobial molecules is an attractive strategy to overcome the low outer membrane permeability of Gram-negative bacteria. In this Trojan horse approach, the transport of drug conjugates is redirected via TonB-dependent receptors (TBDR), which are involved in the uptake of essential nutrients, including iron. Previous reports have demonstrated the involvement of the TBDRs PiuA and PirA from Pseudomonas aeruginosa and their orthologues in Acinetobacter baumannii in the uptake of siderophore-beta-lactam drug conjugates. By in silico screening, we further identified a PiuA orthologue, termed PiuD, present in clinical isolates, including strain LESB58. The piuD gene in LESB58 is located at the same genetic locus as piuA in strain PAO1. PiuD has a similar crystal structure as PiuA and is involved in the transport of the siderophore-drug conjugates BAL30072, MC-1, and cefiderocol in strain LESB58. To screen for additional siderophore-drug uptake systems, we overexpressed 28 of the 34 TBDRs of strain PAO1 and identified PfuA, OptE, OptJ, and the pyochelin receptor FptA as novel TBDRs conferring increased susceptibility to siderophore-drug conjugates. The existence of a TBDR repertoire in P. aeruginosa able to transport siderophore-drug molecules potentially decreases the likelihood of resistance emergence during therapy.
dc.format.extent11
dc.format.extent932011
dc.language.isoeng
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen
dc.subjectPseudomonas aeruginosaen
dc.subjectSiderophore-drug conjugateen
dc.subjectTonB-dependent receptoren
dc.subjectRM Therapeutics. Pharmacologyen
dc.subjectQR Microbiologyen
dc.subjectPharmacologyen
dc.subjectPharmacology (medical)en
dc.subjectInfectious Diseasesen
dc.subjectDASen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.subject.lccRMen
dc.subject.lccQRen
dc.titleTonB-dependent receptor repertoire of pseudomonas aeruginosa for uptake of siderophore-drug conjugatesen
dc.typeJournal articleen
dc.contributor.sponsorEuropean Commissionen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.identifier.doi10.1128/AAC.00097-18
dc.description.statusPeer revieweden
dc.identifier.grantnumberIMI-JU-6-2012en


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