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Light-Activated Metal-Dependent Protein Degradation: A Heterobifunctional Ruthenium(II) Photosensitiser Targeting New Delhi Metallo-β-lactamase 1

Title	Light-Activated Metal-Dependent Protein Degradation: A Heterobifunctional Ruthenium(II) Photosensitiser Targeting New Delhi Metallo-β-lactamase 1
Authors	Lars Stevens-Cullinane, Thomas W. Rees, Calum Evans, Po-Yu Ho, Mika Kintzel, Yew Mun Yip, Ruoning Jia, Jonathan Bailey, Eleanor Clifford, Ruqaiya Alam, Sarah Maslen, Stephane Mouilleron, Adrien Pasquier, Ok-Ryul Song, Scott Warchal, Joanna Redmond, Michael Howell, Svend Kjær, Mark Skehel, Manuel M. Müller, Eachan O. Johnson, Maxie M. Roessler, Jeannine Hess
Magazine	Journal of the American Chemical Society
Date	11/27/2025
DOI	10.1021/jacs.5c12405
Introduction	Antimicrobial resistance poses a significant global health risk, yet the development of new antibiotic drugs remains stagnant. Current clinical compounds are largely from established classes, against which bacteria have developed resistance. Innovative therapeutics are crucial to tackle this issue. Targeted protein degradation, exemplified by proteolysis-targeting chimeras (PROTACs), shows potential but is hindered by the complex requirement for cellular proteolytic recruitment. This study introduces a novel technique utilising a light-activated ruthenium complex, LAMP-D (Light-Activated Metal-dependent Protein Degradation), which eliminates the need for ligase recruitment. This method offers precise spatial and temporal control over protein degradation and can potentially target other proteins. In this proof-of-concept study, New Delhi metallo-β-lactamase 1 (NDM-1) is targeted by LAMP-D. NDM-1, prevalent globally, is used by Gram-negative bacteria to hydrolyse β-lactam antibiotics and is a key clinical target. In vitro assays demonstrate that the Ru1 complex improves NDM-1 inhibition by over 100-fold under light exposure (450 nm, 20 J cm–2). SDS-PAGE and mass spectrometry analyses reveal that Ru1 specifically degrades proteins near the active site. In Escherichia coli expressing NDM-1, Ru1 reduced meropenem MIC by 53-fold with light irradiation (450 nm, 60 J cm–2) and showed no toxicity to mammalian cells.
Quote	Lars Stevens-Cullinane, Thomas W. Rees and Calum Evans et al. Light-Activated Metal-Dependent Protein Degradation: A Heterobifunctional Ruthenium(II) Photosensitiser Targeting New Delhi Metallo-β-lactamase 1. J. Am. Chem. Soc. 2025. Vol. 147(49):44860-44874. DOI: 10.1021/jacs.5c12405
Element	Ruthenium (Ru)
Materials	Chemical Compounds
Industry	Pharmaceutical Industry

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