First Penicillin-Binding Protein Occupancy Patterns of beta-Lactams and beta-Lactamase Inhibitors in Klebsiella pneumoniae.

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Sutaria DS, Moya B, Green KB, Kim TH, Tao X, Jiao Y, Louie A, Drusano GL, Bulitta JB

First Penicillin-Binding Protein Occupancy Patterns of beta-Lactams and beta-Lactamase Inhibitors in Klebsiella pneumoniae.

Antimicrob Agents Chemother. 2018 May 25;62(6). pii: AAC.00282-18. doi: 10.1128/AAC.00282-18. Print 2018 Jun.

PubMed ID

29712652 [ View in PubMed

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Abstract

Penicillin-binding proteins (PBPs) are the high-affinity target sites of all beta-lactam antibiotics in bacteria. It is well known that each beta-lactam covalently binds to and thereby inactivates different PBPs with various affinities. Despite beta-lactams serving as the cornerstone of our therapeutic armamentarium against Klebsiella pneumoniae, PBP binding data are missing for this pathogen. We aimed to generate the first PBP binding data on 13 chemically diverse and clinically relevant beta-lactams and beta-lactamase inhibitors in K. pneumoniae PBP binding was determined using isolated membrane fractions from K. pneumoniae strains ATCC 43816 and ATCC 13883. Binding reactions were conducted using beta-lactam concentrations from 0.0075 to 256 mg/liter (or 128 mg/liter). After beta-lactam exposure, unbound PBPs were labeled by Bocillin FL. Binding affinities (50% inhibitory concentrations [IC50]) were reported as the beta-lactam concentrations that half-maximally inhibited Bocillin FL binding. PBP occupancy patterns by beta-lactams were consistent across both strains. Carbapenems bound to all PBPs, with PBP2 and PBP4 as the highest-affinity targets (IC50, <0.0075 mg/liter). Preferential PBP2 binding was observed by mecillinam (amdinocillin; IC50, <0.0075 mg/liter) and avibactam (IC50, 2 mg/liter). Aztreonam showed high affinity for PBP3 (IC50, 0.06 to 0.12 mg/liter). Ceftazidime bound PBP3 at low concentrations (IC50, 0.06 to 0.25 mg/liter) and PBP1a/b at higher concentrations (4 mg/liter), whereas cefepime bound PBPs 1 to 4 at more even concentrations (IC50, 0.015 to 2 mg/liter). These PBP binding data on a comprehensive set of 13 clinically relevant beta-lactams and beta-lactamase inhibitors in K. pneumoniae enable, for the first time, the rational design and optimization of double beta-lactam and beta-lactam-beta-lactamase inhibitor combinations.

DrugBank Data that Cites this Article

Drugs

Ceftazidime

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ceftazidime	Penicillin-binding protein 1A	Protein	Escherichia coli (strain K12)	Yes	Inhibitor	Details
Ceftazidime	Penicillin-binding protein 1B	Protein	Escherichia coli (strain K12)	Yes	Inhibitor	Details
Ceftazidime	Penicillin-binding protein 2	Protein	Escherichia coli (strain K12)	Yes	Inhibitor	Details
Ceftazidime	Peptidoglycan synthase FtsI	Protein	Escherichia coli (strain K12)	Yes	Inhibitor	Details