Efficacy of imipenem combined with dimercaptosuccinic acid in a murine sepsis model using Pseudomonas aeruginosa

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Infection with metallo β-lactamase (MBL)-producing Pseudomonas aeruginosa poses a global health challenge due to its multidrug resistance and the paucity of available antibiotic therapies. Because MBL-producing P. aeruginosa requires zinc ions to hydrolyze β-lactams, it is proposed that meso-dimercaptosuccinic acid (DMSA), a heavy metal chelator, may bind to the zinc ions of the MBL active site necessary for its activity. The bactericidal and synergistic activity of imipenem plus DMSA was studied against the PAO1 reference strain of P. aeruginosa and five isogenic PAO1 strains producing the MBLs NDM-1, IMP-1, IMP-10, IMP-13, and VIM-2. The efficacy of imipenem and DMSA alone or in combination was tested in a murine model of peritoneal sepsis. In vitro, combination with DMSA increased the activity of imipenem against all MBL-producing strains and had a synergistic effect. In a murine peritoneal sepsis model, we found that combination with DMSA improved the efficacy of imipenem for NDM-1- and IMP-producers.

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