Oligopeptides as full-length New Delhi metallo-β-lactamase-1 (NDM-1) inhibitors

Abstract

'Superbug' bacteria producing NDM-1 enzyme causing wide public concern were first detected in a patient who visited India in 2008. It's an effective approach to combining β-lactam antibiotics with NDM-1 inhibitor for treating NDM-1 producing strain infection. In our research, we designed ten oligopeptides, tested IC50 values against NDM-1 enzyme, determined the MIC values of synergistic antibacterial effect and explored the binding model. We found that the oligopeptides 2 (Cys-Phe) and 5 (Cys-Asp) respectively presented IC50 values of 113 μM and 68 μM and also displayed favorable synergistic effects of the inhibitors in combination with ertapenem against genetic engineering-host E. coli BL21 (DE3)/pET30a-NDM-1 and a clinical isolate of P. aeruginosa with blaNDM-1. Flexible docking and partial charge study suggested the interaction between oligopeptide and NDM-1. Three types of action effects, hydrogen bond, electrostatic effect and π-π interaction, contributed to the inhibitory activities.

Fig 1. Molecular structure of all oligopeptides against NDM-1.

Fig 2. Binding model between inhibitor and target of NDM-1 enzyme.

Binding models of the docked NDM-1 with oligopeptides 2 (Fig 2A) and 5 (Fig 2B), respectively. Structures of inhibitors were shown in stick model. NDM-1 was shown as ribbon model. Six key amino acids binding two zinc ions are colored by pink.

Fig 3. The best pose of inhibitor docked into the active site of NDM-1.

Oligopeptides 2 (Fig 3A) and 5 (Fig 3B) are shown as stick model. Water-bridge and two zinc ions are shown as sphere model (red and black, respectively). Seven key amino acids in catalytic center of NDM-1 (His189, His120, His122, Asp124, Cys208, His250 and Tyr229) treated as flexible residues are shown as line model.

Fig 4. The partial charge values of water-bridge, two zinc ions, and critical atoms of inhibitors.

Oligopeptides 2 (Fig 4A) and 5 (Fig 4B) are shown as stick model, which sulfur atom and oxygen atom are colored by yellow and red, respectively. Water-bridge and two zinc ions are shown as sphere model (red and black, respectively).