Structure-Based Design of β-Lactamase Inhibitors. 1. Synthesis and Evaluation of Bridged Monobactams

• Published in: Journal of medicinal chemistry Vol. 41; no. 21; pp. 3961 - 3971
• Main Authors: Heinze-Krauss, Ingrid, Angehrn, Peter, Charnas, Robert L, Gubernator, Klaus, Gutknecht, Eva-Maria, Hubschwerlen, Christian, Kania, Malgosia, Oefner, Christian, Page, Malcolm G. P, Sogabe, Satoshi, Specklin, Jean-Luc, Winkler, Fritz
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 08-10-1998
• Subjects: Acylation; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; beta-Lactam Resistance; beta-Lactamase Inhibitors; beta-Lactamases - metabolism; Binding Sites; Biological and medical sciences; Ceftriaxone - pharmacology; Cephalosporins - pharmacology; Citrobacter freundii - drug effects; Citrobacter freundii - enzymology; Drug Design; Drug Synergism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; Escherichia coli - enzymology; Kinetics; Medical sciences; Models, Molecular; Molecular Conformation; Monobactams - chemical synthesis; Monobactams - metabolism; Monobactams - pharmacology; Pharmacology. Drug treatments; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - enzymology; Pseudomonadales; Nitrogen heterocycle; Escherichia coli; Active site; Lactam; β-Lactamase; Citrobacter freundii; Modeling; Sodium Compounds; Structure activity relation; Molecular model; Bicyclic compound; Binding mode; Bacteria; Pseudomonadaceae; Pseudomonas aeruginosa; Chemical synthesis; Enterobacteriaceae; Enzyme; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Organic salt; Hydrolases; Antibacterial agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980023c

Bridged monobactams are novel, potent, mechanism-based inhibitors of class C β-lactamases, designed using X-ray crystal structures of the enzymes. They stabilize the acyl−enzyme intermediate by blocking access of water to the enzyme−inhibitor ester bond. Bridged monobactams are selective class C β-lactamase inhibitors, with half-inhibition constants as low as 10 nM, and are less effective against class A and class B enzymes (half-inhibition constants > 100 μM) because of the different hydrolysis mechanisms in these classes of β-lactamases. The stability of the acyl−enzyme complexes formed with class C β-lactamases (half-lives up to 2 days were observed) enabled determination of their crystal structures. The conformation of the inhibitor moiety was close to that predicted by molecular modeling, confirming a simple reaction mechanism, unlike those of known β-lactamase inhibitors such as clavulanic acid and penam sulfones, which involve secondary rearrangements. Synergy between the bridged monobactams and β-lactamase-labile antibiotics could be observed when such combinations were tested against strains of Enterobacteriaceae that produce large amounts of class C β-lactamases. The minimal inhibitory concentration of the antibiotic of more than 64 mg/L could be decreased to 0.25 mg/L in a 1:4 combination with the inhibitor.