Growing challenges with antibiotic resistance pose immense challenges in combating microbial infections and biofilm prevention on medical devices. Lately, antibacterial photodynamic therapy (aPDT) is now emerging as an alternative therapy to overcome this problem. Herein, we synthesized and characterized four Ru(II)-complexes, viz., [Ru(ph-tpy)(bpy)Cl]PF6 (Ru1), [Ru(ph-tpy)(dpq)Cl]PF6 (Ru2), [Ru(ph-tpy)(dppz)Cl]PF6 (Ru3), and [Ru(ph-tpy)(dppn)Cl]PF6 (Ru4) (where 4\'-phenyl-2,2\':6\',2″-terpyridine = ph-tpy; 2,2\'-bipyridine = bpy; dipyrido[3,2-f:2\',3\'-h]quinoxaline = dpq; dipyrido[3,2-a:2\',3\'-c]phenazine = dppz; and Benzo[I]dipyrido[3,2-a:2\',3\'-c]phenazine = dppn), among which Ru2-Ru4 are novel. Octahedral geometry of the complexes with a RuN5Cl core was evident from the crystal structure of Ru2. Ru1-Ru4 showed an MLCT absorption band in the 450-600 nm region, useful for aPDT performances. Further, optimum triplet excited state energy and excellent photostability of Ru1-Ru4 made them good photosensitizers for aPDT. Ru1-Ru4 demonstrated enhanced antimicrobial activity on visible-light exposure (400-700 nm, 10 J cm-2), confirmed using different antibacterial assays. Mechanistic studies revealed that inhibition of bacterial growth was due to the generation of oxidative stress (via NADH oxidation and ROS generation) upon treatment with Ru2-Ru4, resulting in destruction of the bacterial wall. Ru2 performed best killing performance against both Gram-negative (Escherichia coli) and Gram-positive (Bacillus subtilis) bacteria when exposed to light. Ru2-Ru4, when coated on a polydimethylsiloxane (PDMS) disk, showed long-term reusability and durable antibiofilm properties. Molecular docking confirmed the efficient interaction of Ru2-Ru4 with FabH (regulates fatty acid biosynthesis of E. coli) and PgaB (gives structural stability and helps biofilm formation of E. coli), resulting in probable downregulation. In vivo studies with healthy Wistar rats confirmed the biocompatibility of Ru2. This study shows that these lead complexes (Ru2-Ru4) can be used as potent alternative antimicrobial agents in low concentrations toward bacterial eradication with photodynamic therapy (PDT).

The abuse and overuse of antibiotics let drug-resistant bacteria emerges. Antibacterial photodynamic therapy (APDT) has shown outstanding merits to eliminate the drug-resistant bacteria via cytotoxic reactive oxygen species produced by irradiating photosensitizer. However, most of photosensitizers are not effective for Gram-negative bacteria elimination. Herein conjugates of NBS, a photosensitizer, linked with one (NBS-DPA-Zn) or two (NBS-2DPA-Zn) equivalents of zinc-dipicolylamine (Zn-DPA) have been designed to achieve the functional recognition of different bacteria. Due to the cationic character of NBS and metal transfer channel effect of Zn-DPA, NBS-DPA-Zn exhibited the first regent to distinguish P. aeruginosa from other Gram-negative bacteria. Whereas NBS-2DPA-Zn showed broad-spectrum antibacterial effect because the two arm of double Zn-DPA enhanced interactions with anionic membranes of bacteria, led the bacteria aggregation and thus provided the efficacy of APDT to bacteria and corresponding biofilm. In combination with a hydrogel of Pluronic, NBS-2DPA-Zn@gel shows promising clinical application in mixed bacterial diabetic mouse model infection. This might propose a new method that can realize functional identification and elimination of bacteria through intelligent regulation of Zn-DPA, and shows excellent potential for antibacterial application.

Methicillin-resistant Staphylococcus aureus (MRSA) causes great health hazards to society because most antibiotics are ineffective. Photodynamic treatment (PDT) has been proposed to combat MRSA due to the advantage of imaging-guided no-drug resistance therapy. However, the traditional photosensitizers for PDT are limited by aggregation-caused quenching for imaging and low photodynamic antibacterial efficiency. In this work, we synthesize a new aggregation-induced emission (AIE) photosensitizer (APNO), which can ultrafast distinguish between Gram-positive and Gram-negative bacteria within 3 s by AIE-active photosensitizer imaging. Meanwhile, APNO can generate antibacterial reactive oxygen species under light irradiation, which holds potential for antibacterial PDT. Then, APNO is loaded by PHEAA hydrogel to obtain a highly efficient photodynamic hydrogel (APNO@gel). In vitro results show complete inhibition of MRSA by APNO@gel under lower-power light irradiation. Transcriptome analysis is performed to investigate antibacterial mechanism of APNO@gel. Most importantly, APNO@gel also exhibits significant inhibition and killing ability of MRSA in the MRSA wound infection model, which will further promote rapid wound healing. Therefore, the photodynamic hydrogel provides a promising strategy toward MRSA ultrafast imaging and killing.

Herein, we describe the 3\'-sialyllactose-polyethyleneimine-chlorine e6 conjugate (3PC), meticulously engineered to effectively target Helicobacter bacteria (H. pylori) within the gastric environment. The composition of 3PC comprises polyethyleneimine, a cationic polymer, 3\'-sialyllactose, which exhibits a specific binding affinity for H. pylori surface proteins, and a photosensitizer capable of generating oxygen radicals in response to specific wavelengths. The distinctive feature of 3PC lies in its capacity to enhance interaction with the anionic mucus layer facilitated by electrostatic forces. This interaction results in prolonged residence within the intestinal environment. The extended vacation in the intestinal milieu overcomes inherent limitations that have historically impeded conventional antibiotics from efficiently reaching and targeting H. pylori. 3PC can be harnessed as a potent tool for antibacterial photodynamic therapy, and its versatility extends to addressing the challenges posed by various antibiotic-resistant strains. The exceptional efficacy of 3PC in enhancing intestinal residence time and eradicating H. pylori has been robustly substantiated in animal models, particularly in mice. In summary, 3PC is a formidable agent capable of eradicating H. pylori, irrespective of its antibiotic resistance status, by efficiently penetrating and selectively targeting the mucus layer within the gastric environment.

Photothermal treatment (PTT) has emerged as a promising avenue for biofilm elimination, yet its potential drawbacks, such as local hyperpyrexia and bacterial heat resistance, have posed challenges. To address these concerns, an innovative nanoplatform (Au@mSiO2 -arg/ICG) is devised that integrates phototherapeutic and gas therapeutic functionalities. This multifaceted nanoplatform is composed of mesoporous silica-coated Au nanorods (Au@mSiO2 ), supplemented with l-arginine (l-arg) and indocyanine green (ICG), and is engineered for mild temperature PTT aimed at biofilm eradication. Au@mSiO2 -arg/ICG nanoparticles (NPs) show excellent antibacterial effects through the generation of nitric oxide (NO) gas, heat, and reactive oxygen species (ROS) under 808 nm light irradiation. The ROS generated by ICG initiates a cascade reaction with l-arg, ultimately yielding NO gas molecules. This localized release of NO not only effectively curbs the expression of heat shock proteins 70 mitigating bacterial thermoresistance, but also reduces extracellular polymeric substance allowing better penetration of the therapeutic agents. Furthermore, this nanoplatform achieves an outstanding biofilm elimination rate of over 99% in an abscess model under 808 nm light irradiation (0.8 W·cm-2 ), thereby establishing its potential as a dependable strategy for NO-enhanced mild PTT and antibacterial photodynamic therapy (aPDT) in clinical settings.

Bacterial wound infection has emerged as a pivotal threat to human health worldwide, and the situation has worsened owing to the gradual increase in antibiotic-resistant bacteria caused by the improper use of antibiotics. To reduce the use of antibiotics and avoid the increase in antibiotic-resistant bacteria, researchers are increasingly paying attention to  photodynamic therapy, which uses light to produce reactive oxygen species to kill bacteria. Treating bacteria-infected wounds by photodynamic therapy requires fixing the photosensitizer (PS) at the wound site and maintaining a certain level of wound humidity. Hydrogels are materials with a high water content and are well suited for fixing PSs at wound sites for antibacterial photodynamic therapy. Therefore, hydrogels are often loaded with PSs for treating bacteria-infected wounds via antibacterial photodynamic therapy. In this review, we systematically summarised the antibacterial mechanisms and applications of PS-loaded hydrogels for treating bacteria-infected wounds via photodynamic therapy. In addition, the recent  studies and the research status progresses of novel antibacterial hydrogels are discussed. Finally, the challenges and future prospects of PS-loaded hydrogels are reviewed.

Antibacterial photodynamic therapy (APDT) has emerged as one of the intriguing strategies to combat bacterial resistance. However, the antibacterial efficacy of APDT is found to be severely impacted by the hydrogen sulfide (H2 S)-overproduced bacterial infection microenvironment. Herein, a multifunctional APDT platform is developed by assembling Cu2+ and chlorin e6 (Ce6), which exhibits unique H2 S-activatable fluorescence (FL) and antibacterial features. Noteworthily, the assembly conditions are crucial for achievement of Cu-Ce6 nanoassemblies (NAs) with the on-demand responsive properties. The quenched FL and photosensitization of Cu-Ce6 NAs can be selectively activated by the overexpressed H2 S in infected area, enabling specific recognition of bacterial infection and localized antibacterial therapy with minimized side effects. Significantly, amplified oxidative stress is achieved owning to the effective consumption of H2 S by Cu2+ in the NAs, leading to an enhanced APDT. The antibacterial mechanisms including broad-spectrum APDT activity of released Ce6, inherent sterilization effects of produced copper polysulfides and the accompanying disturbance of bacterial sulphide metabolism are further identified. This study may pave a new avenue for the rational design of intelligent APDT platform using minimalist biological building units and thus facilitating the clinical translation of nano-antibacterial agents.

Intracellular Staphylococcus aureus (S. aureus), especially the methicillin resistant staphylococcus aureus (MRSA), are difficult to detect and eradicate due to the protection by the host cells. Antibacterial photodynamic therapy (aPDT) offers promise in treating intracellular bacteria, provided that selective damage to the bacteria ranther than host cells can be realized. According to the different nitroreductase (NTR) levels in mammalian cells and S. aureus, herein NTR-responsive photosensitizers (PSs) (T)CyI-NO2 were designed and synthesized. The emission and 1O2 generation of (T)CyI-NO2 are quenched by the 4-nitrobenzyl group, but can be specifically switched on by bacterial NTR. Therefore, selective imaging and photo-inactivation of intracellular S. aureus and MRSA were achieved. Our findings may pave the way for the development of more efficient and selective aPDT agents to combat intractable intracellular infections.

Due to the antibiotics abuse, bacterial infection has become one of the leading causes of human death worldwide. Novel selective antimicrobial agents are urgently needed, with the hope of maintaining the balance of the microbial environment. Photo-activated chemotherapeutics have shown great potential to eliminate bacteria with appealing spatiotemporal selectivity. In this work, we reported the structural modification to enhance the triplet excited state property of Rhodamine B, synthesizing a rhodamine-based photosensitizer RBPy. Upon light activation, RBPy exhibited much stronger photosensitization ability than the parent compound Rhodamine B both in solution and in bacteria. Importantly, RBPy can selectively inactivate Staphylococcus aureus and inhibit biofilm formation with high biocompatibility. This work provides a new strategy to develop rhodamine-based photoactive chemotherapeutics for antimicrobial photodynamic therapy.

Photodynamic therapy has always been an antibacterial tool for solving multi-drug resistant bacteria problem, but the side effects and the low efficiency due to the high aggregation and low solubility of photosensitizers limit its application. Due to the anti-inflammatory effect of caffeic acid, two novel photosensitizers (CA-1-TBO, CA-TBO) were synthesized by conjugating caffeic acid with toluidine blue O (TBO). The structures have been characterized by 1HNMR and high-resolution mass spectrometry. The UV-vis absorption, fluorescence spectra and the octanol-water partition coefficient of two photosensitizers were measured to evaluate their photophysical properties and hydrophilic/hydrophobic properties. Compared with parent TBO, the two modified photosensitizers have shown a higher quantum yield and kinetics constants of singlet oxygen, which has been supported by the simulation results of density functional theory. As drug-resistant representatives of gram-positive and gram-negative bacteria, respectively, S. aureus and P. aeruginosa have been used for in vitro antibacterial experiments. The sterilization efficiencies of the two modified photosensitizers far exceed that of parent TBO. The results of the octanol-water partition coefficient and fluorescence quantification showed that modified photosensitizers CA-1-TBO and CA-TBO could be more accumulated than parent TBO. Based on scanning electron microscopy images, protein gel electrophoresis, and the conductivity of the bacterial solution, the possible mechanism of improved antibacterial photodynamic efficiencies could be induced by membrane permeability due to the caffeic acid effect. The findings demonstrate the significant potential of natural phenolic compounds in the development of photosensitizer molecules with characteristics such as more efficient, biocompatible and less side effects.