Structure-based design of beta-lactamase inhibitors. 1. Synthesis and evaluation of bridged monobactams.
Bridged monobactams are novel, potent, mechanism-based inhibitors of class C beta-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 beta-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 microM) because of the different hydrolysis mechanisms in these classes of beta-lactamases. The stability of the acyl-enzyme complexes formed with class C beta-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 beta-lactamase inhibitors such as clavulanic acid and penam sulfones, which involve secondary rearrangements. Synergy between the bridged monobactams and beta-lactamase-labile antibiotics could be observed when such combinations were tested against strains of Enterobacteriaceae that produce large amounts of class C beta-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.
Heinze-Krauss
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Preclinical Research, F. Hoffmann-La Roche Ltd., CH-4070 Basle, Switzerland.
Angehrn
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Charnas
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Gubernator
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Gutknecht
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Hubschwerlen
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Kania
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Oefner
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Page
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Sogabe
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Specklin
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Winkler
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D000215:Acylation; D001665:Binding Sites; D002443:Ceftriaxone / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D016971:Citrobacter freundii / Q000187:drug effects / Q000201:enzymology; D015195:Drug Design; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D008997:Monobactams / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D002511:Cephalosporins; D004791:Enzyme Inhibitors; D008997:Monobactams; D065093:beta-Lactamase Inhibitors; D002443:Ceftriaxone; D001618:beta-Lactamases