STRUCTURE-BASED DESIGN OF BETA-LACTAMASE INHIBITORS - 1 - SYNTHESIS AND EVALUATION OF BRIDGED MONOBACTAMS

Bridged monobactams are novel, potent, mechanism-based inhibitors of c lass C beta-lactamases, designed using X-ray crystal structures of the enzymes. They stabilize the acyl-enzyme intermediate by blocking acce ss of water to the enzyme-inhibitor ester bond. Bridged monobactams ar e selective class C beta-lactamase inhibitors, with half-inhibition co nstants as low as 10 nM, and are less effective against class A and cl ass B enzymes (half-inhibition constants > 100 mu M) because of the di fferent hydrolysis mechanisms in these classes of beta-lactamases. The stability of the acyl-enzyme complexes formed with class C beta-lacta mases (half-lives up to 2 days were observed) enabled determination of their crystal structures. The conformation of the inhibitor moiety wa s close to that predicted by molecular modeling, confirming a simple r eaction mechanism, unlike those of known beta-lactamase inhibitors suc h as clavulanic acid and penam sulfones, which involve secondary rearr angements. Synergy between the bridged monobactams and beta-lactamase- labile antibiotics could be observed when such combinations were teste d against strains of Enterobacteriaceae that produce large amounts of class C beta-lactamases. The minimal inhibitory concentration of the a ntibiotic of more than 64 mg/L could be decreased to 0.25 mg/L in a 1: 4 combination with the inhibitor.