Light-Activated Metal-Dependent Protein Degradation: a heterobifunctional ruthenium(II) photosensitizer targeting New Delhi metallo-β-lactamase 1
Author(s)
Type
Journal Article
Abstract
Antimicrobial resistance (AMR) is a global health threat, yet, despite this, antibiotic drug discovery has stagnated. Most compounds entering the clinic represent already discovered classes, to which bacteria already display resistance. We urgently need novel therapeutics to address this. Targeted protein degradation, typified by proteolysis-targeting chimeras (PROTACs), is a promising approach that has already seen success in oncology. A significant hurdle faced by these methods, however, is the complexity inherent in recruiting the host cell’s proteolytic processes. We herein describe an approach where proteolysis is performed by a light-activated ruthenium complex, termed LAMP-D (Light-Activated Metal-dependent Protein Degradation), thus circumventing the need for ligase recruitment. This method allows precise spatiotemporal control of protein degradation and may be adapted to degrade other proteins of interest. In a proof-of-concept study, New Delhi metallo-β-lactamase 1 (NDM-1) was chosen as a target for LAMP-D. NDM-1 is employed by Gram-negative bacteria to hydrolyze β-lactam antibiotics and is considered one of the most clinically relevant β-lactamase targets due to its global prevalence. In in vitro assays, the complex Ru1 demonstrated a greater than 100-fold improvement in NDM-1 inhibition on exposure to light (450 nm, 20 J cm–2). Detailed analyses by SDS-PAGE and mass spectrometry show that Ru1 induces highly specific degradation of the protein adjacent to the active site. Ru1 was shown to inhibit NDM-1 in Escherichia coli expressing NDM-1 and demonstrated a 53-fold improvement in meropenem MIC with light irradiation (450 nm, 60 J cm–2). Furthermore, the complex exhibited no toxicity toward mammalian cells.
Date Issued
2025-12-10
Date Acceptance
2025-10-21
Citation
Journal of the American Chemical Society, 2025, 147 (49), pp.44860-44874
ISSN
0002-7863
Publisher
American Chemical Society
Start Page
44860
End Page
44874
Journal / Book Title
Journal of the American Chemical Society
Volume
147
Issue
49
Copyright Statement
Copyright © 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 .
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41308195
Subjects
ACCUMULATION
BROAD
Chemistry
Chemistry, Multidisciplinary
COMPLEXES
DERIVATIVES
DNA
IMPACT
INACTIVATION
MITOCHONDRIA
PHOTODYNAMIC THERAPY
Physical Sciences
POTENT
Science & Technology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2025-11-27