Camel-Derived Nanobodies as Potent Inhibitors of New Delhi Metallo-β-Lactamase-1 Enzyme

TL;DR

Camel-derived nanobodies show strong potential as inhibitors of the NDM-1 enzyme, which is a major cause of antibiotic resistance in Gram-negative bacteria.

Contribution

The study identifies nanobodies as novel, potent inhibitors of the NDM-1 enzyme with nanomolar inhibitory activity.

Findings

Three nanobodies (Nb02NDM-1, Nb12NDM-1, and Nb17NDM-1) act as uncompetitive inhibitors of NDM-1.

Nb02NDM-1 and Nb17NDM-1 have IC50 values of 25.0 nM and 8.5 nM, respectively.

Nanobodies show promise for combating Gram-negative bacterial infections.

Abstract

The injudicious usage of antibiotics during infections caused by Gram-negative bacteria leads to the emergence of β-lactamases. Among them, the NDM-1 enzyme poses a serious threat to human health. Developing new antibiotics or inhibiting β-lactamases might become essential to reduce and prevent bacterial infections. Nanobodies (Nbs), the smallest antigen-binding single-domain fragments derived from Camelidae heavy-chain-only antibodies, targeting enzymes, are innovative alternatives to develop effective inhibitors. The biopanning of an immune VHH library after phage display has helped to retrieve recombinant antibody fragments with high inhibitory activity against recombinant-NDM-1 enzyme. Nb02NDM-1, Nb12NDM-1, and Nb17NDM-1 behaved as uncompetitive inhibitors against NDM-1 with Ki values in the nM range. Remarkably, IC50 values of 25.0 nM and 8.5 nM were noted for Nb02NDM-1 and Nb17NDM-1, respectively. The promising inhibition of NDM-1 by Nbs highlights their potential application in combating particular Gram-negative infections.

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