Synthesis and Evaluation of Carbapenem/Metallo-β-Lactamase Inhibitor Conjugates

Antibiotics, particularly the beta-lactams, are a cornerstone of modern medicine. However, the rise of bacterial resistance to these agents, particularly through the actions of beta-lactamases, poses a significant threat to our continued ability to effectively treat infections. Metallo-beta-lactamases (MBLs) are of particular concern due to their ability to hydrolyze a wide range of beta-lactam antibiotics including carbapenems. For this reason there is growing interest in the development of MBL inhibitors as well as novel antibiotics that can overcome MBL-mediated resistance. Here, we report the synthesis and evaluation of novel conjugates that combine a carbapenem (meropenem or ertapenem) with a recently reported MBL inhibiting indole carboxylate scaffold. These hybrids were found to display potent inhibition against MBLs including NDM-1 and IMP-1, with IC50 values in the low nanomolar range. However, their antibacterial potency was limited. Mechanistic studies suggest that despite maintaining effective MBL inhibiting activity in live bacteria, the new carbapenem/MBL inhibitor conjugates have a reduced ability to engage with the bacterial target of the beta-lactams. We report the synthesis and evaluation of molecular conjugates that combine a carbapenem antibiotic (meropenem or ertapenem) with a recently reported indole carboxylate scaffold. These hybrids are potent inhibitors of metallo-beta-lactamases including the clinically relevant NDM-1 and IMP-1 enzymes. image