Synthesis and evaluation of carbapenem/metallo‐β‐lactamase inhibitor conjugates

Abstract

Antibiotics, particularly the β‐lactams, are a cornerstone of modern medicine. However, the rise of bacterial resistance to these agents, particularly through the actions of β‐lactamases, poses a significant threat to our continued ability to effectively treat infections. Metallo‐β‐lactamases (MBLs) are of particular concern due to their ability to hydrolyze a wide range of β‐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 β‐lactams.