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

Abstract

AbstractResistance to antibiotics is increasing worldwide, necessitating urgent action to sustain the efficacy of existing antibiotics in clinical use. We show that tannic acid (TA) in combination with carbapenems can reduce and/or reverse the minimum inhibitory concentrations (MICs) of carbapenems to susceptible values in Enterobacteriaceae that express class A and B carbapenemases. MICs of carbapenems in the presence and absence of TA and other efflux pump inhibitors, TA-carbapenemases inhibition assays and computational studies were undertaken to determine the effect of TA on carbapenem susceptibility in Enterobacteriaceae. TA had the greatest effect on metallo-β-lactamases (MBLs) followed by class A serine-β-lactamases (SBLs). Antibiotic susceptibility testing showed that TA reversed the MICs of MBLs to susceptible values whilst substantially reducing the MICs of SBLs (class A). Tolerable cytotoxicity effect was observed for the concentrations tested. TA inhibited enzymes with a marked difference between ≈50% inhibition (IC50) for NDM-1 and KPC-2. Computational studies including molecular docking, molecular dynamics simulations and binding free energy calculations showed that TA interact with both MBLs and SBLs hydrophobic sites. Moreover, TA had a stronger binding affinity for MBLs than SBLs as the MBLs, specifically VIM-1 and NDM-1, interact with a larger number of their catalytic active-site residues than that of OXA- 48 and KPC-2. These in vitro evaluations together with computational simulation explain the potentiating effect of TA toward carbapenems against carbapenem-resistance enterobacteriaceae. This study proposes TA as a promising adjuvant for MBLs and SBLs.