Inhibition of the Class C β-Lactamase from Acinetobacter spp.: Insights into Effective Inhibitor Design

• Published in: Biochemistry (Easton) 2010-01, Vol.49 (2), p.329-340
• Main Authors: Drawz, Sarah M, Babic, Maja, Bethel, Christopher R, Taracila, Magda, Distler, Anne M, Ori, Claudia, Caselli, Emilia, Prati, Fabio, Bonomo, Robert A
• Format: Article
• Language: English
• Subjects: Acinetobacter - enzymology; beta-Lactamase Inhibitors; beta-Lactamases - chemistry; beta-Lactamases - metabolism; Carbapenems - chemistry; Carbapenems - pharmacology; Cephalosporinase - chemistry; Cephalothin - chemistry; Cephalothin - pharmacology; Drug Design; Escherichia coli - drug effects; Gram-Negative Bacteria - enzymology; Kinetics; Microbial Sensitivity Tests; Models, Molecular; Penicillinase - chemistry; Penicillinase - metabolism; Protein Conformation; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi9015988

The need to develop β-lactamase inhibitors against class C cephalosporinases of Gram-negative pathogens represents an urgent clinical priority. To respond to this challenge, five boronic acid derivatives, including a new cefoperazone analogue, were synthesized and tested against the class C cephalosporinase of Acinetobacter baumannii [Acinetobacter-derived cephalosporinase (ADC)]. The commercially available carbapenem antibiotics were also assayed. In the boronic acid series, a chiral cephalothin analogue with a meta-carboxyphenyl moiety corresponding to the C3/C4 carboxylate of β-lactams showed the lowest K i (11 ± 1 nM). In antimicrobial susceptibility tests, this cephalothin analogue lowered the ceftazidime and cefotaxime minimum inhibitory concentrations (MICs) of Escherichia coli DH10B cells carrying bla ADC from 16 to 4 μg/mL and from 8 to 1 μg/mL, respectively. On the other hand, each carbapenem exhibited a K i of