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Molecular Basis of AmpC beta-Lactamase Induction by Avibactam in Pseudomonas aeruginosa: PBP Occupancy, Live Cell Binding Dynamics and Impact on Resistant Clinical Isolates Harboring PDC-X Variants

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dc.contributor.authorLopez-Arguello, Silvia
dc.contributor.authorMontaner, Maria
dc.contributor.authorOliver, Antonio
dc.contributor.authorMoya, Bartolome
dc.date.accessioned2024-09-18T06:43:46Z
dc.date.available2024-09-18T06:43:46Z
dc.date.issued2021-03
dc.description.abstractAvibactam belongs to the new class of diazabicyclooctane beta-lactamase inhibitors. Its inhibitory spectrum includes class A, C and D enzymes, including P. aeruginosa AmpC. Nonetheless, recent reports have revealed strain-dependent avibactam AmpC induction. In the present work, we wanted to assess the mechanistic basis underlying AmpC induction and determine if derepressed PDC-X mutated enzymes from ceftazidime/avibactam-resistant clinical isolates were further inducible. We determined avibactam concentrations that half-maximally inhibited (IC50) bocillin FL binding. Inducer beta-lactams were also studied as comparators. Live cells' time-course penicillin-binding proteins (PBPs) occupancy of avibactam was studied. To assess the ampC induction capacity of avibactam and comparators, qRT-PCR was performed in wild-type PAO1, PBP4, triple PBP4, 5/6 and 7 knockout derivatives and two ceftazidime/avibactam-susceptible/resistant XDR clinical isolates belonging to the epidemic high-risk clone ST175. PBP4 inhibition was observed for avibactam and beta-lactam comparators. Induction capacity was consistently correlated with PBP4 binding affinity. Outer membrane permeability-limited PBP4 binding was observed in the live cells' assay. As expected, imipenem and cefoxitin showed strong induction in PAO1, especially for carbapenem; avibactam induction was conversely weaker. Overall, the inducer effect was less remarkable in ampC-derepressed mutants and nonetheless absent upon avibactam exposure in the clinical isolates harboring mutated AmpC variants and their parental strains.en
dc.description.sponsorshipB.M. received funds from RADIX17/3-1 fellowship and RADIX17/3-2 grant, program within the FUTURMed project IdISBa Research Institute of Health Sciences of the Balearic Islands, Hospital Universitario Son Espases, Palma, Spain. Sustainable Tourism Tax, Govern de les Illes Balears and by the Miguel Servet Research Contract Program CP20/00138. A.O. received funds from the Ministerio de Economia y Competitividad of Spain, Instituto de Salud Carlos III, cofinanced by the European Regional Development Fund A way to achieve Europe ERDF, through the Spanish Network for the Research in Infectious Diseases (RD16/0016).es_ES
dc.format.number6es_ES
dc.format.page3051es_ES
dc.format.volume22es_ES
dc.identifier.citationLopez-Arguello S, Montaner M, Oliver A, Moya B. Molecular Basis of AmpC beta-Lactamase Induction by Avibactam in Pseudomonas aeruginosa: PBP Occupancy, Live Cell Binding Dynamics and Impact on Resistant Clinical Isolates Harboring PDC-X Variants. Int J Mol Sci. 2021 Mar;22(6):3051.en
dc.identifier.doi10.3390/ijms22063051
dc.identifier.e-issn1422-0067es_ES
dc.identifier.journalInternational Journal of Molecular Scienceses_ES
dc.identifier.otherhttps://hdl.handle.net/20.500.13003/19696
dc.identifier.pubmedID33802668es_ES
dc.identifier.puiL2006752296
dc.identifier.scopus2-s2.0-85102571546
dc.identifier.urihttps://hdl.handle.net/20.500.12105/23282
dc.identifier.wos645730200001
dc.language.isoengen
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)
dc.relation.publisherversionhttps://dx.doi.org/10.3390/ijms22063051en
dc.rights.accessRightsopen accessen
dc.rights.licenseAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectPenicillin-binding proteins
dc.subjectPBP
dc.subjectAvibactam
dc.subjectAmpC induction
dc.subjectPDC
dc.subjectβ-lactam resistance
dc.subjectST175
dc.subject.decsConcentración 50 Inhibidora*
dc.subject.decsImipenem*
dc.subject.decsProteínas de Unión a las Penicilinas*
dc.subject.decsRegulación Bacteriana de la Expresión Génica*
dc.subject.decsFarmacorresistencia Bacteriana*
dc.subject.decsMutación*
dc.subject.decsCefoxitina*
dc.subject.decsCompuestos de Azabiciclo*
dc.subject.decsPruebas de Sensibilidad Microbiana*
dc.subject.decsHumanos*
dc.subject.decsProteínas Bacterianas*
dc.subject.decsPseudomonas aeruginosa*
dc.subject.decsbeta-Lactamasas*
dc.subject.meshBacterial Proteins*
dc.subject.meshMicrobial Sensitivity Tests*
dc.subject.meshHumans*
dc.subject.meshPenicillin-Binding Proteins*
dc.subject.meshDrug Resistance, Bacterial*
dc.subject.meshInhibitory Concentration 50*
dc.subject.meshCefoxitin*
dc.subject.meshMutation*
dc.subject.meshAzabicyclo Compounds*
dc.subject.meshbeta-Lactamases*
dc.subject.meshGene Expression Regulation, Bacterial*
dc.subject.meshPseudomonas aeruginosa*
dc.subject.meshImipenem*
dc.titleMolecular Basis of AmpC beta-Lactamase Induction by Avibactam in Pseudomonas aeruginosa: PBP Occupancy, Live Cell Binding Dynamics and Impact on Resistant Clinical Isolates Harboring PDC-X Variantsen
dc.typeresearch articleen
dspace.entity.typePublication
relation.isPublisherOfPublication30293a55-0e53-431f-ae8c-14ab01127be9
relation.isPublisherOfPublication.latestForDiscovery30293a55-0e53-431f-ae8c-14ab01127be9

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