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In vitro potentiation of carbapenems with tannic acid against carbapenemase‐producing enterobacteriaceae: exploring natural products as potential carbapenemase inhibitors

A.M. Somboro, J. Osei Sekyere, D.G. Amoako, H.M. Kumalo, R. Khan, L.A. Bester, S.Y. Essack
Journal of applied microbiology 2019 v.126 no.2 pp. 452-467
Enterobacteriaceae, active sites, adjuvants, beta-lactamase, binding capacity, carbapenems, cytotoxicity, enzyme inhibition, enzyme inhibitors, hydrophobicity, inhibitory concentration 50, minimum inhibitory concentration, tannins, transporters
AIMS: We hypothesized and confirmed that tannic acid (TA) reverses carbapenem resistance by inhibiting carbapenemases in class A and B carbapenemase‐producing Enterobacteriaceae. METHODS AND RESULTS: Minimum inhibitory concentrations of carbapenems in the presence and absence of TA and other efflux pump inhibitors, TA‐carbapenemases inhibition assays and computational studies showed that TA had the greatest effect on metallo‐β‐lactamases (MBLs) followed by class A serine‐β‐lactamases (SBLs). TA completely reversed the MICs of MBL producers from between 32 and ≥512 mg l⁻¹ to susceptible values (<4 mg l⁻¹) while substantially reducing the MICs of SBLs from between 16 and >512 mg l⁻¹ to <4 to 16 mg l⁻¹. Tolerable cytotoxic effect was observed for the concentrations tested (8–1024 mg l⁻¹). TA inhibited enzymes with a marked difference of ≈50% inhibition (IC₅₀) for NDM‐1 (270 μmol l⁻¹) and KPC‐2 (15 μmol l⁻¹). CONCLUSION: TA inhibited both MBLs and SBLs by targeting their hydrophobic sites. Moreover, TA had a stronger binding affinity for MBLs than SBLs as the MBLs, specifically VIM‐1 (−43·7220 ± 0·4513 kcal mol⁻¹) and NDM‐1(−44·2329 ± 0·3806 kcal mol⁻¹), interact with a larger number of their catalytic active‐site residues than that of OXA‐48 (−22·5275 ± 0·1300 kcal mol⁻¹) and KPC‐2 (−22·1164 ± 0·0111 kcal mol⁻¹). SIGNIFICANCE AND IMPACT OF THE STUDY: Tannic acid or its analogues could be developed into carbapenemase‐inhibiting adjuvants to restore carbapenem activity in CRE infections, save many lives and reduce healthcare associated costs.