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oai:repisalud.isciii.es:20.500.12105/232822024-11-29T01:27:26Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Lopez-Arguello, Silvia author Montaner, Maria author Oliver, Antonio author Moya, Bartolome author 2021-03 Avibactam 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. Lopez-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. 10.3390/ijms22063051 1422-0067 International Journal of Molecular Sciences https://hdl.handle.net/20.500.13003/19696 33802668 L2006752296 2-s2.0-85102571546 https://hdl.handle.net/20.500.12105/23282 645730200001 Penicillin-binding proteins PBP Avibactam AmpC induction PDC β-lactam resistance ST175 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