Thiol-Containing Metallo-β-Lactamase Inhibitors Resensitize Resistant Gram-Negative Bacteria to Meropenem

The prevalence of infections caused by metallo-β-lactamase (MBL) expressing Gram-negative bacteria has grown at an alarming rate in recent years. Despite the fact that MBLs can deactivate virtually all β-lactam antibiotics, there are as of yet no approved drugs available that inhibit their activity. We here examine the ability of previously reported thiol-based MBL inhibitors to synergize with meropenem and cefoperazone against a panel of Gram-negative carbapenem-resistant isolates expressing different β-lactamases. Among the compounds tested, thiomandelic acid 3 and 2-mercapto-3-phenylpropionic acid 4 were found to efficiently potentiate the activity of meropenem, especially against an imipenemase (IMP) producing strain of K. pneumoniae. In light of the zinc-dependent hydrolytic mechanism employed by MBLs, biophysical studies using isothermal titration calorimetry were also performed, revealing a correlation between the synergistic activity of thiols 3 and 4 and their zinc-binding ability with measured Kd values of 9.8 and 20.0 μM, respectively.