Open AccessNovel Cephalosporin Conjugates Display Potent and Selective Inhibition of Imipenemase-Type Metallo-β-Lactamases
Author(s) -
Kamaleddin Haj Mohammad Ebrahim Tehrani,
Nicola Wade,
Vida Mashayekhi,
Nora Brüchle,
Willem Jespers,
Koen Voskuil,
Diego Pesce,
Matthijs J. van Haren,
Gerard J. P. van Westen,
Nathaniel I. Martin
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00362
Subject(s) - chemistry , prodrug , conjugate , moiety , cephalosporin , stereochemistry , hydrolysis , combinatorial chemistry , enzyme , structure–activity relationship , cephalosporin antibiotic , biochemistry , antibiotics , in vitro , mathematical analysis , mathematics
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.