Inhibitory activity of meso-dimercaptosuccinic acid against IMP metallo-<i>β</i>-lactamase variants in <i>Pseudomonas aeruginosa</i>

The treatment of infections caused by MBL-producing Pseudomonas aeruginosa, including IMP-producers, can be challenging since MBLs confer resistance to most clinically available ß-lactams, leaving few viable options. Thiol-containing compounds, such as meso-dimercaptosuccinic acid (DMSA), have been suggested as inhibitors of MBLs, and particularly have been proposed to exert effective activity against IMP-1 enzymes. In this context, we sought to determine the activity of DMSA, in combination with carbapenems or cephalosporins, against diverse MBL and carbapenemase variants, particularly focussing on IMP variants. In recombinant strains producing either IMP-1, IMP-10, or IMP-13, both with and without a functional OprD, synergy was observed with ceftazidime (CAZ), cefepime (FEP), and meropenem. Negligible changes were observed for other MBLs and no effect was observed in stains producing KPC-2. Testing of the CAZ/DMSA and FEP/DMSA combinations against clinical IMP-producing P. aeruginosa isolates resulted in fractional inhibitory concentration indexes indicating synergy. Enzymatic assays showed a significantly increased inhibitory activity of DMSA against the IMP variants, compared to the other enzymes tested. These findings highlight a possible role of DMSA or DMSA-like compounds to be developed for the treatment of infections caused by IMP-producing P. aeruginosa.