Infectious diseases continue to pose one of the most significant challenges to global healthcare. Traditionally, antibiotics have been the primary approach for controlling, treating, and preventing bacterial infections. However, the growing prevalence of antibiotic-resistant “superbugs”, especially in hospital settings, has become an escalating concern in recent years [1,2]. Furthermore, biofilms formed by microbial communities and their extracellular polymeric substances (EPS) contribute to heightening the antibiotic resistance and persistent infections [3].

Antimicrobial photodynamic therapy (aPDT) is a non-invasive technique used to eliminate pathogenic microorganisms, including bacteria, viruses, fungi, and protists. It employs photosensitizers (PSs) activated by specific wavelengths of light to produce singlet oxygen and other reactive oxygen species (ROS) [4]. These ROS can inflict oxidative damage on multiple cellular targets, including nucleic acids, lipids, and proteins [5,6]. ROS could oxidize the cell components including unsaturated fatty acids in membranes, polysaccharides, amino acids (e.g. cysteine, tyrosine) in proteins, and nucleic acids (e.g. causing base oxidation and strand breaks) [7,8], compromising membrane integrity, enzymatic functions, genetic stability, and structural support [[9], [10], [11]]. The broad-spectrum oxidative mechanisms of ROS underpin the efficacy of aPDT while preventing the development of resistance [[12], [13], [14]]. Thus, aPDT has been considered a promising alternative to antibiotics for treating bacterial infections in some localized tissues (e.g., oral peri-implant infections) or inactivating pathogenic microorganisms in blood products.

Bacterial cell walls contain negatively charged components that generate anionic sites, such as teichoic acids in Gram-positive bacteria and lipopolysaccharides with phosphate groups in Gram-negative bacteria. The primary structural constituents of bacterial biofilms are EPS, which encompass polysaccharides, proteins, and extracellular DNA [15]. Many of these molecules carry carboxyl, phosphate, and other functional groups that contribute to their negative charge. The electrostatic interaction between these with negatively charged components and cationic photosensitizers facilitates the accumulation of PSs on bacterial surfaces, leading to enhanced photodynamic antibacterial efficiency compared to neutral or anionic compounds [16,17]. Some cationic PSs with various positively charged substituents, including pyridinium and ammonium groups, were synthesized and their antibacterial effects were observed. These PSs are primarily activated by light sources emitting within the 400–550 nm wavelength range [[18], [19], [20], [21], [22]].

The wavelength of the photoactivation light is crucial for aPDT. Light with wavelengths in the red region are particularly suitable for photodynamic therapy due to its deeper tissue penetration compared to shorter wavelengths [23]. Tetranaphtho[2,3]porphyrin (TNP) is a class of π-extended porphyrins with four pyrrole units fused with exocyclic naphthalene groups. Our previous studies have shown that TNPs have long wavelength absorption and excellent ROS generation capabilities [24,25]. To discover versatile antimicrobial PSs with high ROS generation capability and strong affinity for bacterial cell walls and biofilms, a series of new Ar4TNPs with cationic substituents at the periphery chains of the meso-phenyl fragment were synthesized. Their photodynamic inactivation efficacy against Staphylococcus aureus, Escherichia coli and Candida albicans was evaluated, alongside safety evaluations on HaCaT human keratinocyte cell lines.