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Novel Cephalosporin Conjugates Display Potent and Selective Inhibition of IMP Type Metallo-β-Lactamases
preprintsubmitted on 07.12.2020, 16:46 and posted on 08.12.2020, 13:15 by Kamaleddin Tehrani, Nicola Wade, Vida Mashayekhi, Nora Brüchle, Willem Jespers, Koen Voskuil, Diego Pesce, Matthijs J. van Haren, Gerard van Westen, Nathaniel Martin
In an attempt to exploit the hydrolytic mechanism by which β-lactamase enzymes degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-β-lactamases (MBLs) in spatiotemporally controlled fashion. Notably, while enzyme-mediated hydrolysis of the β-lactam ring was found to occur, it was not accompanied by release of the thiol-based inhibitors. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (8), demonstrated potent inhibition of IMP-type MBLs, with IC50 values in the nanomolar range. In addition, conjugate 8 was also found to greatly reduce the MIC of meropenem against an IMP-28 producing clinical isolate of K. pneumoniae. 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 residues Trp28 and Lys161 within the IMP active site may contribute to the observed inhibitory potency and selectivity.