In vitro evaluation of metal chelators as potential metallo- -lactamase inhibitors

AimsThis study aimed at investigating the use of metal chelators as potential metallo--lactamase inhibitors (MBL). Methods and ResultsThe minimum inhibitory concentration (MIC) of meropenem was ascertained alone and in combination with various concentrations of macrocyclic (1,4,7- triazacyclononane-1-glutaric acid-4,7-diacetic acid=NODAGA) peptide derivatives and acyclic (N,N,N,N-Tetrakis(2-pyridylmethyl)ethylenediamine=TPEN and di-(2-picolyl)amine=DPA) metal chelators using the broth microdilution method. MICs of meropenem against carbapenem-resistant enterobacteriaceae (CRE) producing MBLs were decreased to concentrations as low as 006mgl(-1) in the presence of some metal chelators. TPEN at 4 and 8mgl(-1) showed the best activity by decreasing meropenem MICs to 05 and 006mgl(-1), respectively, for some New Delhi Metallo-beta-lactamase (NDM) and Verona integron-encoded metallo--lactamase (VIM) -producing enterobacteriaceae. DPA at 8 and 16mgl(-1) was also able to decrease meropenem MICs to 1 and 0125mgl(-1), respectively, for these CREs. NODAGA peptide derivatives showed the least inhibition as 32mgl(-1) was required for meropenem MICs to be decreased to 006mgl(-1) against an NDM-1 producing isolate. ConclusionThe various metal chelators, TPEN, DPA and NODAGA peptide derivatives were able to inhibit the MBLs in decreasing order of activity, rendering CREs susceptible to meropenem. Significance and Impact of the StudyIn the absence of new antibiotics, this study evaluated metal chelators as potential MBL inhibitors.