Dimercaptosuccinic acid in combination with carbapenems against isogenic strains of Escherichia coli producing or not producing a metallo-β-lactamase in vitro and in murine peritonitis.

Background: Carbapenemase-producing Enterobacterales represent a major therapeutic challenge. MBLs, requiring zinc at their catalytic site, could be inhibited by meso-dimercaptosuccinic acid (DMSA), a heavy metal chelator already widely used for treating Lead intoxication. Objectives: To evaluate the activity of carbapenems done or combined with DMSA against MBL-producing Escherichia coli in a severe murine peritonitis model. Methods: Isogenic strains of wild-type E. coli CFT073 producing the MBLs NDM-1, VIM-2 and IMP-1, and the controi serine carbapenemases OXA-48 and KPC-3 were constructed. MIC determinations and time-kiLL assays were performed for imipenem, meropenem and ertapenem done or in combination with DMSA. Infected mice were treated intraperitoneafly for 24 h with imipenem, DMSA or their combination. Bacterial counts in peritoneaL fluid and spleen were assessed at 24 h. Results: DMSA in combination with each carbapenem caused a significant decrease in the MICs for all MBL-producing strains, in a concentration-dependent manner, but did not provide benefit against non-MBL strains. In mice infected with the NDM-1-producing strain, the combination of imipenem and DMSA significantly reduced bacterial counts in peritoneal fluid (P=0.0006) and spleen (P< 0.0001), as compared with imipenem done, with no benefit against the KPC-3-producing and CFT073 strains. DMSA concentrations in plasma of mice were comparable to those obtained in humans with a standard oral dose. Conclusions: DMSA restores the activity of carbapenems against MBL-producing strains, and its combination with carbapenems appears to be a promising strategy for the treatment of NDM-producing E. coli infections.