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bioRxiv · 10.1101/2020.06.01.126664

Molecular Bases of the Membrane Association Mechanism Potentiating Antibiotic Resistance by New Delhi Metallo--Lactamase 1

Prunotto, A.·Bahr, G.·Gonzalez, L. J.·Vila, A. J.·Dal Peraro, M.
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Abstract

Resistance to last-resort carbapenem antibiotics is an increasing threat to human health, as it critically limits therapeutic options. Metallo-{beta}-lactamases are the largest family of carbapenemases, enzymes that inactivate these drugs. Among MBLs, New Delhi metallo-{beta}-lactamase 1 has experienced the fastest and largest worldwide dissemination. This success has been attributed to the fact that NDM-1 is a lipidated protein anchored to the outer membrane of bacteria, while all other MBLs are soluble periplasmic enzymes. By means of a combined experimental and computational approach, we show that NDM-1 interacts with the surface of bacterial membranes in a stable, defined conformation, in which the active site is not occluded by the bilayer. Although the lipidation is required for a long-lasting interaction, the globular domain of NDM-1 is tuned to interact specifically with the outer bacterial membrane. In contrast, this affinity is not observed for VIM-2, a natively soluble MBL. Finally, we identify key residues involved in the membrane interaction of NDM-1, which constitute potential targets for developing therapeutic strategies able to combat resistance granted by this enzyme.

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Prunotto, A., Bahr, G., Gonzalez, L. J., Vila, A. J., Dal Peraro, M.. 2020-06-01. Molecular Bases of the Membrane Association Mechanism Potentiating Antibiotic Resistance by New Delhi Metallo--Lactamase 1. https://doi.org/10.1101/2020.06.01.126664

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