Zinc Chelator N,N,N',N'-Tetrakis(2-Pyridylmethyl)Ethylenediamine Reduces the Resistance of to Imipenem.

PURPOSE

Imipenem is one of the very few effective options for treating () infections; the development of imipenem resistance is a major health concern.

MATERIALS AND METHODS

The susceptibility of 194 clinical isolates to imipenem was determined. The ability of imipenem to synergize with N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a zinc chelator and a metallo-β-lactamases (MBLs) inhibitor, to inhibit growth was also assessed.

RESULTS

exhibited an elevated resistance to imipenem (MIC = 16 mg/L, MIC = 64 mg/L). A combination of TPEN and imipenem synergized to inhibit the growth of 100% of imipenem-resistant and 79.2% of imipenem-resistance intermediate isolates; no synergy was observed treating imipenem-sensitive isolates. A remarkable decrease in the MIC (from 16 to 4 mg/L) and MIC (from 64 to 8 mg/L) of imipenem was observed when it was combined with TPEN; the portion of imipenem-resistant isolates also decreased (from 48.4% to 0%). Consistent with these results demonstrating synergy, a time-kill assay showed the addition of TPEN significantly improved the bactericidal activity of imipenem toward . Similarly, EDTA (a potent MBLs inhibitor) promoted the anti- activity of imipenem in a disk assay, corroborating the effect of TPEN and supporting the role of MBLs in imipenem resistance exhibited by some isolates.

CONCLUSION

These findings demonstrate that TPEN can reduce the resistance of to imipenem and suggest that the inhibition of MBLs activity is the underlying mechanism.