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

Author:

Ben Abderrazek Rahma1,Hamdi Emna12ORCID,Piccirilli Alessandra2,Dhaouadi Sayda1,Muyldermans Serge3ORCID,Perilli Mariagrazia2ORCID,Bouhaouala-Zahar Balkiss14ORCID

Affiliation:

1. Laboratoire des Biomolécules Venins et Applications Théranostiques, Institut Pasteur Tunis, 13 Place Pasteur, Tunisie Université Tunis El Manar, B.P N 93, Tunis 1068, Tunisia

2. Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università degli Studi dell’Aquila, Via Veteoio Coppito, 67100 L’Aquila, Italy

3. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleenlaan, 9, 1050 Brussels, Belgium

4. Faculté de Médecine de Tunis, Université Tunis El Manar, B.P N 93, Tunis 1068, Tunisia

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.

Funder

Ministry of High Education and Scientific Research of Tunisia

Ministry of Health, Pasteur Institute of Tunis: Internal Collaborative Program

Federative National Project

Department of Biotechnological and Applied Clinical Sciences of the University of L’Aquila: intramural DISCAB

Publisher

MDPI AG

Reference43 articles.

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