Cheminet, G. de Lastours, V. Poirel, Laurent Chau, F. Peoc’h, K. Massias, L. Fantin, B. Nordmann, Patrice 2020-12-01 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 alone 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 control serine carbapenemases OXA-48 and KPC-3 were constructed. MIC determinations and time–kill assays were performed for imipenem, meropenem and ertapenem alone or in combination with DMSA. Infected mice were treated intraperitoneally 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 alone, 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. application/pdf https://folia.unifr.ch/global/documents/309105 https://folia.unifr.ch/documents/309105/files/nor_dac.pdf https://folia.unifr.ch/documents/309105/files/nor_dac_sm.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1093/jac/dkaa347 info:eu-repo/semantics/openAccess License undefined Journal of Antimicrobial Chemotherapy. - 2020, vol. 75, no. 12, p. 3593–3600 carbapenem peritoneal fluid imipenem peritonitis plasma succimer infections mice spleen zinc escherichia coli beta-lactamase ndm-1 malnutrition-inflammation-cachexia syndrome info:eu-repo/classification/udc/57 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 http://purl.org/coar/resource_type/c_6501