Inhibition of Class A β-Lactamases

The catalytic function of β-lactamases is the primary mechanism of bacterial resistance to β-lactam antibiotics (penicillins, cephalosporins, carbapenems). β-lactamases hydrolyze the β-lactam bond of these antibiotics, a structure modification that abrogates the antibacterial activity. β-lactams include tazobactam, a highly effective sulfone penam inhibitor, penicillanic acid sulfone sulbactam, 6-β-bromopenicillanic acid, and thienamycin. Clavulanate is a potent inhibitor of class A β-lactamases, which incidentally exhibits weak antimicrobial activity as well. A series of molecules-using sulfoxide and sulfone penams have been synthesized as starting points-with sulfhydryl and sulfide moieties at C-6; the goal of this exercise was to arrive at molecules that would simultaneously inhibit classes A and B of β-lactamases. The study also confirmed that the sulfone oxidation state of the penam thiazolidine resulted in greater inhibition. The success of BRL 42715 prompted additional efforts into compounds with a double bond at C-6, leading to the discovery of SYN-1012-with a methyl triazolyl moiety at C6 instead-and another more recent methylidene penem-with a bicyclic and heterocyclic moiety at C-6; both of these compounds show good activity against class A and C β-lactamases. Several routes have been taken towards the development of more effective inhibitors including the syntheses of variants of penam sulfones, penems, alkylidenes, monobactams, transition-state analogs, and the boronates.