A luminescent antibacterial compound targeting Gram-negative bacterial membrane

Abstract

Infections caused by multidrug-resistant (MDR) Gram-negative bacteria represent a critical global health challenge, necessitating the urgent identification of new antibacterial targets to improve drug discovery and development. In this study, we designed and synthesized a series of triphenylamine compounds based on the skeleton of the aggregation-induced emission luminogen (AIEgen) compound TTVP. Among a series of candidate compounds, we acquired the pathogen-tracking probe TTCVP that exhibits strong antibacterial activity against Gram-negative bacteria. TTCVP can realise real-time monitoring of both extracellular and intracellular bacteria with excellent photostability and biocompatibility. Structure and activity relationship study shows that the broad-spectrum activity of TTCVP against both MDR Gram-negative and Gram-positive bacteria depends on the cationic charge density, hydrophilic linker, and the increased number of positively charged pyridine moieties of photosensitizer. Mechanistic studies indicate that TTCVP selectively binds to the fatty acid chain of phospholipids within the bacterial inner membrane, resulting in membrane function perturbation and inducing reactive oxygen species (ROS) accumulation to kill the pathogens. Our findings highlight TTCVP as a promising photosensitizer against Gram-negative bacterial infections and present a potential approach to both therapy and target discovery.