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-beta-lactamases (MBLs) followed by class A serine-beta-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 approximate to 50% inhibition (IC50) for NDM-1 (270 mu mol l(-1)) and KPC-2 (15 mu mol 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.