Details

Autor(en) / Beteiligte

• Sutaria, Dhruvitkumar S
• Moya, Bartolome
• Green, Kari B
• Kim, Tae Hwan
• Tao, Xun
• Jiao, Yuanyuan
• Louie, Arnold
• Drusano, George L
• Bulitta, Jürgen B

Titel

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

Ist Teil von

• Antimicrobial agents and chemotherapy, 2018-06, Vol.62 (6)

Ort / Verlag

United States: American Society for Microbiology

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

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