Sam Benson†,1,2,✉, Alex Kiang†,1, Charles Lochenie1,2, Navita Lal1, Syam Mohan P. C. Mohanan1, Gareth O. S. Williams1, Kevin Dhaliwal1, Bethany Mills1,✉, Marc Vendrell1,2,✉
1. Centre for Inflammation Research, The University of Edinburgh, Edinburgh EH16 4TJ, UK. 2. IRR Chemistry Hub, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4UU, UK. †These authors contributed equally.
Bacterial infections remain among the biggest challenges to human health, leading to high antibiotic usage, morbidity, hospitalizations, and accounting for approximately 8 million deaths worldwide every year. The overuse of antibiotics and paucity of antimicrobial innovation has led to antimicrobial resistant pathogens that threaten to reverse key advances of modern medicine. Photodynamic therapeutics can kill bacteria but there are few agents that can ablate pathogens with minimal off-target effects.
Methods: We describe nitrobenzoselenadiazoles as some of the first environmentally sensitive organic photosensitizers, and their adaptation to produce theranostics with optical detection and light-controlled antimicrobial activity. We combined nitrobenzoselenadiazoles with bacteria-targeting moieties (i.e., glucose-6-phosphate, amoxicillin, vancomycin) producing environmentally sensitive photodynamic agents.
Results: The labelled vancomycin conjugate was able to both visualize and eradicate multidrug resistant Gram-positive ESKAPE pathogens at nanomolar concentrations, including clinical isolates and those that form biofilms.
Conclusion: Nitrobenzoselenadiazole conjugates are easily synthesized and display strong environment dependent ROS production. Due to their small size and non-invasive character, they unobtrusively label antimicrobial targeting moieties. We envisage that the simplicity and modularity of this chemical strategy will accelerate the rational design of new antimicrobial therapies for refractory bacterial infections.
Benson S, Kiang A, Lochenie C, Lal N, Mohanan SMPC, Williams GOS, Dhaliwal K, Mills B, Vendrell M. Environmentally sensitive photosensitizers enable targeted photodynamic ablation of Gram-positive antibiotic resistant bacteria. Theranostics 2023; 13(11):3814-3825. doi:10.7150/thno.84187. https://www.thno.org/v13p3814.htm
Benson S, Kiang A, Lochenie C, Lal N, Mohanan SMPC, Williams GOS, Dhaliwal K, Mills B, Vendrell M. 2023. Environmentally sensitive photosensitizers enable targeted photodynamic ablation of Gram-positive antibiotic resistant bacteria. Theranostics. 13(11):3814-3825.
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