Novel Cephalosporin Conjugates Display Potent and Selective Inhibition of Imipenemase-Type Metallo-β-Lactamases

In an attempt to exploit the hydrolytic mechanism by which beta-lactamases degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-beta-lactamases (MBLs) in a spatiotemporally controlled fashion. While enzymatic hydrolysis of the beta-lactam ring was observed, it was not accompanied by inhibitor release. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (8), demonstrated potent inhibition of IMP-type MBLs. In addition, conjugate 8 was also found to greatly reduce the minimum inhibitory concentration of meropenem against IMP-producing bacteria. The results of kinetic experiments indicate that these prodrugs inhibit IMP-type MBLs by acting as slowly turned-over substrates. Structure-activity relationship studies revealed that both phenyl and carboxyl moieties of 8 are crucial for its potency. Furthermore, modeling studies indicate that productive interactions of the thiomandelic acid moiety of 8 with Trp28 within the IMP active site may contribute to its potency and selectivity.

Automated summary

The novel cephalosporin prodrugs designed to inhibit metallo-beta-lactamases have shown potential, especially the thiomandelic acid conjugate (8). Conjugate 8 not only effectively inhibits IMP-type MBLs, but also significantly reduces the minimum inhibitory concentration of meropenem against IMP-producing bacteria. These prodrugs act as slowly turned-over substrates to inhibit IMP-type MBLs, with the phenyl and carboxyl moieties of crucial importance for potency.