A membrane intercalating metal-free conjugated organic photosensitizer for bacterial photodynamic inactivation

Photodynamic inhibition (PDI) of bacteria represents a powerful strategy for dealing with multidrug-resistant pathogens and infections, as it exhibits minimal development of antibiotic resistance. The PDIaction stems from the generation of a triplet state in the photosensitizer (PS), which subsequentlytransfers energy or electrons to molecular oxygen, resulting in the formation of reactive oxygen species(ROS). These ROS are then able to damage cells, eventually causing bacterial eradication. Enhancing theefficacy of PDI includes the introduction of heavy atoms to augment triplet generation in the PS, as wellas membrane intercalation to circumvent the problem of the short lifetime of ROS. However, the formerapproach can pose safety and environmental concerns, while achieving stable membrane partitioningremains challenging due to the complex outer envelope of bacteria. Here, we introduce a novel PS,consisting of a metal-free donor-acceptor thiophene-based conjugate molecule (BV-1). It presentsseveral advantageous features for achieving effective PDI, namely: (i) it exhibits strong light absorptiondue to the conjugated donor-acceptor moieties; (ii) it exhibits spontaneous and stable membranepartitioning thanks to its amphiphilicity, accompanied by a strong fluorescence turn-on; (iii) it undergoesmetal-free intersystem crossing, which occurs preferentially when the molecule resides in themembrane. All these properties, which we rationalized via optical spectroscopies and calculations,current state-of-the-art treatments. Our approach holds significant potential for the development ofnew PS for controlling bacterial infections, particularly those caused by Gram-negative bacteria.enable the effective eradication of Escherichia coli, with an inhibition concentration that is below that of