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In vitro evaluation of metal chelators as potential metallo‐ β ‐lactamase inhibitors

R. Azumah, J. Dutta, A.M. Somboro, M. Ramtahal, L. Chonco, R. Parboosing, L.A. Bester, H.G. Kruger, T. Naicker, S.Y. Essack, T. Govender
Journal of applied microbiology 2016 v.120 no.4 pp. 860-867
Enterobacteriaceae, chelating agents, in vitro studies, meropenem, minimum inhibitory concentration, India
AIMS: This study aimed at investigating the use of metal chelators as potential metallo‐β‐lactamase inhibitors (MBL). METHODS AND RESULTS: The 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 0·06 mg l⁻¹ in the presence of some metal chelators. TPEN at 4 and 8 mg l⁻¹ showed the best activity by decreasing meropenem MICs to 0·5 and 0·06 mg l⁻¹, respectively, for some New Delhi Metallo‐beta‐lactamase (NDM) and Verona integron‐encoded metallo‐β‐lactamase (VIM) ‐producing enterobacteriaceae. DPA at 8 and 16 mg l⁻¹ was also able to decrease meropenem MICs to 1 and 0·125 mg l⁻¹, respectively, for these CREs. NODAGA peptide derivatives showed the least inhibition as 32 mg l⁻¹ was required for meropenem MICs to be decreased to 0·06 mg l⁻¹ against an NDM‐1 producing isolate. CONCLUSION: The 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 STUDY: In the absence of new antibiotics, this study evaluated metal chelators as potential MBL inhibitors.