In Vitro Potentiation of Carbapenems with Tannic Acid Against Carbapenemase Producing Enterobacteriaceae: Exploring Natural Products as Potential Carbapenemase Inhibitors.

AIMS: We hypothesised and confirmed that tannic acid (TA) reverses carbapenem resistance by inhibiting carbapenemases in class A and B carbapenemase-producing Enterobacteriaceae.

METHODS AND RESULTS: MICs 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- ≥512mg/L to susceptible values (< 4mg/L) whilst substantially reducing the MICs of SBLs from between 16- > 512mg/L to <4-16mg/L. Tolerable cytotoxic effect was observed for the concentrations tested (8 - 1024 mg/L). TA inhibited enzymes with a marked difference of ≈50% inhibition (IC50 ) for NDM-1 (270 μM) and KPC-2 (15 μM).

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) and NDM-1(-44.2329±0.3806 kcal/mol), interact with a larger number of their catalytic active-site residues than that of OXA-48 (-22.5275±0.1300 kcal/mol) and KPC-2 (-22.1164±0.0111 kcal/mol).

SIGNIFICANCE AND IMPACT OF 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. This article is protected by copyright. All rights reserved.