Increased susceptibility of multi-drug resistant and wastewater-exposed bacteria to antimicrobial photodynamic inactivation

Antimicrobial resistance (AMR) poses a significant global health threat, necessitating urgent development of novel antimicrobial strategies. Antimicrobial photodynamic inactivation (aPDI), which damages multiple cellular targets simultaneously and therefore reduces the likelihood of resistance development, provides a promising approach. Here, we evaluate the antimicrobial efficacy of structurally modified TMPyP-based photosensitizers (PSs), focusing on the combined effects of metalation and long-chain alkylation against both reference and multidrug-resistant (MDR) ESKAPE pathogens as well as within wastewater matrices. Addition of a 14-carbon alkyl chain significantly improved the antimicrobial activity of a metalated PS, achieving substantial killing of Gram-positive and -negative species under low light dosing conditions. Although the alkylated and non-alkylated analogs exhibited similar singlet oxygen production, increased bacterial association of the alkylated PS suggests that improved cellular interaction drives the increased efficacy. Notably, Gram-negative MDR strains displayed equal or greater susceptibility to aPDI compared to non-resistant counterparts, highlighting the potential of this approach against resistant pathogens. Within wastewater matrices, a zinc-chelated analog (ZnC14) demonstrated effective treatment, significantly reducing both mock and indigenous microbial populations. These findings suggest that combining metalation with amphiphilic modifications enhances aPDI performance and may broaden its applicability as an alternative or complementary strategy against AMR in complex environmental systems.