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


ABSTRACT: In an attempt to exploit the hydrolytic mechanism by which β-lactamases degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-β-lactamases (MBLs) in a spatiotemporally controlled fashion. While enzymatic hydrolysis of the β-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.

SUBMITTER: Tehrani KHME 

PROVIDER: S-EPMC8273888 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Tehrani Kamaleddin H M E KHME   Wade Nicola N   Mashayekhi Vida V   Brüchle Nora C NC   Jespers Willem W   Voskuil Koen K   Pesce Diego D   van Haren Matthijs J MJ   van Westen Gerard J P GJP   Martin Nathaniel I NI  

Journal of medicinal chemistry 20210628 13


In an attempt to exploit the hydrolytic mechanism by which β-lactamases degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-β-lactamases (MBLs) in a spatiotemporally controlled fashion. While enzymatic hydrolysis of the β-lactam ring was observed, it was not accompanied by inhibitor release. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (<b>8</b>), demonstrated potent  ...[more]

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