Development of aggregation-induced emission photosensitizers as antiplanktonic and antibiofilm agents

Abstract

Bacterial infection has always been a clinical challenge to humans. One of the biggest challenges is that bacteria can encase in self-produced extracellular polymeric substances (EPS) to form biofilms. Bacteria encased in biofilms are difficult to kill due to their tolerance to high concentrations of antibiotics that can normally kill planktonic bacteria. With the emergence of antimicrobial resistance (AMR), traditional antibiotics are losing their effectiveness in treating bacterial infections. To cope with this situation, alternative antibacterial strategies, including photodynamic therapy (PDT), have been developed. PDT utilizes a photosensitizer (PS) to generate reactive oxygen species (ROS) under light irradiation. These ROS can damage essential biological components in bacteria without generating AMR. Recently, aggregation-induced emission (AIE) PSs have gained popularity for antibacterial PDT because of their ability to prevent aggregation-caused quenching (ACQ) and enhance ROS generation upon target binding. Despite significant efforts invested over the last decade, AIE PSs with both good antibiofilm activity and biocompatibility remain rare. In this thesis, novel AIE PSs have been developed for antiplanktonic and antibiofilm applications. A water-soluble and bacterial targeting AIE PS, TPA-1, which is a triphenylamine derivative, has been designed and synthesized. TPA-1 has minimal cytotoxicity towards human cells with and without light irradiation. Additionally, TPA-1 exhibits intrinsic antibacterial activity. Without light irradiation, TPA-1 acts as a narrow-spectrum antibacterial agent, eradicating S. aureus and preventing their biofilm formation. Upon light irradiation, TPA-1 effectively eradicates planktonic and biofilm S. aureus and P. aeruginosa. The therapeutic efficacy of TPA-1 has also been assessed with in vivo mice models. Furthermore, the intrinsic antibacterial activity of TPA-1 was improved through structural modifications. Among the modified AIE PSs, TPA-C3-C6 was shown to be the most active AIE PS against S. aureus and P. aeruginosa, even without light irradiation, while maintaining relatively low cytotoxicity. The combined effects of PDT and the intrinsic antibacterial activity of TPA-C3-C6 enhance the antibiofilm activity and prevent biofilm recurrence.