Bacterial DNA-Targeting AIE Photosensitizer for Efficient Eradication of Intracellular Bacteria and Biofilm-Associated Infections

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA), often residing within biofilms and host cells, exhibits heightened resistance to conventional antibiotics and immune clearance, resulting in persistent and recurrent infections. Given the central role of DNA in bacterial proliferation and virulence, it represents an ideal target for the development of next-generation antibacterial agents. In this study, we report the development of a DNA-targeting photosensitizer (PS), TPE-CN, designed for the effective treatment of MRSA-associated infections. TPE-CN demonstrates high specificity for bacterial DNA, along with excellent membrane permeability, enabling disruption of both bacterial DNA and membrane structures. This allows for the efficient eradication of planktonic MRSA. Moreover, TPE-CN can also selectively colocalize with the lysosome of macrophages, facilitating effective eradication of intracellular bacteria while preserving host cell integrity. Furthermore, in vivo studies further validate the potent antimicrobial effects of TPE-CN, resulting in accelerated wound healing in severe MRSA infection models. Collectively, this work presents a novel molecular design strategy for precise bacterial DNA targeting, offering a promising therapeutic avenue for combating drug-resistant pathogens and advancing the development of next-generation antimicrobial therapies.

Keywords

AIE photosensitizer / bacterial infection / DNA targeting / intracellular bacteria / photodynamic therapy

References

[1] F. R. DeLeo, M. Otto, B. N. Kreiswirth, and H. F. Chambers, “Community-Associated Meticillin-Resistant Staphylococcus aureus,” The Lancet 375 (2010): 1557–1568.

[2] M. Maree, L. T. Thi Nguyen, R. L. Ohniwa, M. Higashide, T. Msadek, and K. Morikawa, “Natural Transformation Allows Transfer of SCCmec-Mediated Methicillin Resistance in Staphylococcus aureus Biofilms,” Nature Communications 13 (2022): 2477.

[3] S. M. Lehar, T. Pillow, M. Xu, et al., “Novel Antibody–Antibiotic Conjugate Eliminates Intracellular S. aureus,” Nature 527 (2015): 323–328.

[4] M. Barcia-Macay, C. Seral, M.-P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke, “Pharmacodynamic Evaluation of the Intracellular Activities of Antibiotics Against Staphylococcus aureus in a Model of THP-1 Macrophages,” Antimicrobial Agents and Chemotherapy 50 (2006): 841–851.

[5] A. Sandberg, J. H. Hessler, R. L. Skov, J. Blom, and N. Frimodt-Møller, “Intracellular Activity of Antibiotics Against Staphylococcus aureus in a Mouse Peritonitis Model,” Antimicrobial Agents and Chemotherapy 53 (2009): 1874–1883.

[6] S. Helaine, A. M. Cheverton, K. G. Watson, L. M. Faure, S. A. Matthews, and D. W. Holden, “Internalization of Salmonella by Macrophages Induces Formation of Nonreplicating Persisters,” Science 343 (2014): 204–208.

[7] M. E. Olson and A. R. Horswill, “Staphylococcus aureus Osteomyelitis: Bad to the Bone,” Cell Host & Microbe 13 (2013): 629–631.

[8] M. E. Powers and J. B. Wardenburg, “Igniting the Fire: Staphylococcus aureus Virulence Factors in the Pathogenesis of Sepsis,” PLoS Pathogens 10 (2014): e1003871.

[9] C. Selton-Suty, M. Célard, V. Le Moing, et al., “Preeminence of Staphylococcus aureus in Infective Endocarditis: A 1-Year Population-Based Survey,” Clinical Infectious Diseases 54 (2012): 1230–1239.

[10] N. F. Kamaruzzaman, S. Kendall, and L. Good, “Targeting the Hard to Reach: Challenges and Novel Strategies in the Treatment of Intracellular Bacterial Infections,” British Journal of Pharmacology 174 (2017): 2225–2236.

[11] S. Subramaniam, P. Joyce, N. Thomas, and C. A. Prestidge, “Bioinspired Drug Delivery Strategies for Repurposing Conventional Antibiotics Against Intracellular Infections,” Advanced Drug Delivery Reviews 177 (2021): 113948.

[12] J. R. Pritchard, D. A. Lauffenburger, and M. T. Hemann, “Understanding Resistance to Combination Chemotherapy,” Drug Resistance Updates 15 (2012): 249–257.

[13] Z. Fu, M. Wang, C. Huang, et al., “Flexible Antibacterial Degradable Bioelastomer Nanocomposites for Ultrasensitive Human–Machine Interaction Sensing Enabled by Machine Learning,” Aggregate 5 (2024): e522.

[14] C. Zhou, Z. Ding, W. Guan, and B. Z. Tang, “Self-Reporting Fluorescence Deciphers the Antibacterial Nature of Cationic Amphiphiles: Monomer or Aggregate?” Aggregate 4 (2023): e366.

[15] Z. Tian, S. Zhou, Y. Qu, et al., “Enhanced Synergistic Photothermal–Chemotherapy in Bacterial Keratitis Treatment Using Halogen-Bonded Organic Frameworks (XOFs) Based on N⋯Br⁺⋯N Bonds,” Aggregate 6 (2025): e70050.

[16] S. Mariathasan and M.-W. Tan, “Antibody–Antibiotic Conjugates: A Novel Therapeutic Platform Against Bacterial Infections,” Trends in Molecular Medicine 23 (2017): 135–149.

[17] H. Moroder, J. Steger, D. Graber, et al., “Non-Hydrolyzable RNA–Peptide Conjugates: A Powerful Advance in the Synthesis of Mimics for 3′-Peptidyl tRNA Termini,” Angewandte Chemie International Edition 121 (2009): 4116–4120.

[18] G. Qi, F. Hu, Kenry, L. Shi, M. Wu, and B. Liu, “An AIEgen-Peptide Conjugate as a Phototheranostic Agent for Phagosome-Entrapped Bacteria,” Angewandte Chemie International Edition 58 (2019): 16229–16235.

[19] F. Umstätter, C. Domhan, T. Hertlein, et al., “Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides,” Angewandte Chemie International Edition 59 (2020): 8823–8827.

[20] A. Gupta, S. Mumtaz, C.-H. Li, I. Hussain, and V. M. Rotello, “Combatting Antibiotic-Resistant Bacteria Using Nanomaterials,” Chemical Society Reviews 48 (2019): 415–427.

[21] J. M. V. Makabenta, A. Nabawy, C.-H. Li, S. Schmidt-Malan, R. Patel, and V. M. Rotello, “Nanomaterial-Based Therapeutics for Antibiotic-Resistant Bacterial Infections,” Nature Reviews Microbiology 19 (2021): 23–36.

[22] Y. Wang, Y. Yang, Y. Shi, H. Song, and C. Yu, “Antibiotic-Free Antibacterial Strategies Enabled by Nanomaterials: Progress and Perspectives,” Advanced Materials 32 (2020): 1904106.

[23] X. He, Y. Yang, Y. Guo, et al., “Phage-Guided Targeting, Discriminative Imaging, and Synergistic Killing of Bacteria by AIE Bioconjugates,” Journal of the American Chemical Society 142 (2020): 3959–3969.

[24] A. Petrovic Fabijan, R. C. Lin, J. Ho, et al., “Safety of Bacteriophage Therapy in Severe Staphylococcus aureus Infection,” Nature Microbiology 5 (2020): 465–472.

[25] X. Liu, H. Li, G. Qi, et al., “Combating Fungal Infections and Resistance With a Dual-Mechanism Luminogen to Disrupt Membrane Integrity and Induce DNA Damage,” Journal of the American Chemical Society 146 (2024): 31656–31664.

[26] S. Bai, J. Song, H. Pu, et al., “Chemical Biology Approach to Reveal the Importance of Precise Subcellular Targeting for Intracellular Staphylococcus aureus Eradication,” Journal of the American Chemical Society 145 (2023): 23372–23384.

[27] S. Zhang, M. Shao, Y. Wu, et al., “Novel [3+2+1] Coordinated Iridium (III) Complexes for Hyperefficient Photodynamic Therapy,” Aggregate 6 (2025): e710.

[28] H. Huang, Q. Liu, J.-H. Zhu, et al., “Dimerized Pentamethine Cyanines for Synergistically Boosting Photodynamic/Photothermal Therapy,” Aggregate 6 (2025): e706.

[29] Y. Zhang, C. Qian, Y. Chen, W. He, and Z. Guo, “Phototherapy via Modulation of β-Amyloid in Combating Alzheimer's Disease,” Aggregate 6 (2025): e70020.

[30] D. Mao, F. Hu, G. Qi, et al., “One-Step In Vivo Metabolic Labeling as a Theranostic Approach for Overcoming Drug-Resistant Bacterial Infections,” Materials Horizons 7 (2020): 1138–1143.

[31] Z. Li, S. Lu, W. Liu, et al., “Synergistic Lysozyme-Photodynamic Therapy Against Resistant Bacteria Based on an Intelligent Upconversion Nanoplatform,” Angewandte Chemie International Edition 60 (2021): 19201–19206.

[32] S. Deng, Z. Peng, F. Zhou, et al., “Elaborately Engineered Au(I)-Based AIEgens: Robust and Broad-Spectrum Elimination Abilities Toward Drug-Resistant Bacteria,” Aggregate 5 (2024): e575.

[33] J. Qi, H. Ou, Q. Liu, and D. Ding, “Gathering Brings Strength: How Organic Aggregates Boost Disease Phototheranostics,” Aggregate 2 (2021): 95–113.

[34] Z. Yu, W. Pan, N. Li, and B. Tang, “A Nuclear Targeted Dual-Photosensitizer for Drug-Resistant Cancer Therapy With NIR Activated Multiple ROS,” Chemical Science 7 (2016): 4237–4244.

[35] K. N. Wang, L. Y. Liu, G. Qi, et al., “Light-Driven Cascade Mitochondria-to-Nucleus Photosensitization in Cancer Cell Ablation,” Advanced Science 8 (2021): 2004379.

[36] S. Bai, J. Wang, K. Yang, et al., “A Polymeric Approach Toward Resistance-Resistant Antimicrobial Agent With Dual-Selective Mechanisms of Action,” Science Advances 7 (2021): eabc9917.

[37] E. Oldfield and X. Feng, “Resistance-Resistant Antibiotics,” Trends in Pharmacological Sciences 35 (2014): 664–674.

[38] G. Shi, S. Monro, R. Hennigar, et al., “Ru(II) Dyads Derived From α-Oligothiophenes: A New Class of Potent and Versatile Photosensitizers for PDT,” Coordination Chemistry Reviews 282 (2015): 127–138.

[39] J. Dai, Z.-Q. Liu, X.-Q. Wang, et al., “Discovery of Small Molecules for Up-Regulating the Translation of Antiamyloidogenic Secretase, a Disintegrin and Metalloproteinase 10 (ADAM10), by Binding to the G-Quadruplex-Forming Sequence in the 5′ Untranslated Region (UTR) of Its mRNA,” Journal of Medicinal Chemistry 58 (2015): 3875–3891.

[40] M. Li, H. Wen, H. Li, et al., “AIEgen-Loaded Nanofibrous Membrane as Photodynamic/Photothermal Antimicrobial Surface for Sunlight-Triggered Bioprotection,” Biomaterials 276 (2021): 121007.

[41] Y. Wu, J. Li, Z. Shen, et al., “Double-Pronged Antimicrobial Agents Based on a Donor-π-Acceptor Type Aggregation-Induced Emission Luminogen,” Angewandte Chemie International Edition 61 (2022): e202212386.

[42] Y. Lu, S. Vibhute, L. Li, et al., “Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-Dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead With In Vivo Efficacy Against MRSA,” Journal of Medicinal Chemistry 64 (2021): 15214–15249.

[43] J. Mei, D. Xu, L. Wang, et al., “Biofilm Microenvironment-Responsive Self-Assembly Nanoreactors for All-Stage Biofilm Associated Infection Through Bacterial Cuproptosis-Like Death and Macrophage Re-Rousing,” Advanced Materials 35 (2023): 2303432.

[44] M. Godoy-Gallardo, U. Eckhard, L. M. Delgado, et al., “Antibacterial Approaches in Tissue Engineering Using Metal Ions and Nanoparticles: From Mechanisms to Applications,” Bioactive Materials 6 (2021): 4470–4490.

[45] M. Ibba and D. Söll, “Aminoacyl-tRNA Synthesis,” Annual Review of Biochemistry 69 (2000): 617–650.

[46] C. Yang, Y. Luo, H. Lin, M. Ge, J. Shi, and X. Zhang, “Niobium Carbide MXene Augmented Medical Implant Elicits Bacterial Infection Elimination and Tissue Regeneration,” ACS Nano 15 (2020): 1086–1099.

[47] X. Han, Q. Lou, F. Feng, et al., “Spatiotemporal Release of Reactive Oxygen Species and NO for Overcoming Biofilm Heterogeneity,” Angewandte Chemie International Edition 134 (2022): e202202559.

[48] Z. Liu, K. Guo, L. Yan, et al., “Janus Nanoparticles Targeting Extracellular Polymeric Substance Achieve Flexible Elimination of Drug-Resistant Biofilms,” Nature Communications 14 (2023): 5132.

[49] B. D. Jones and S. Falkow, “SALMONELLOSIS: Host Immune Responses and Bacterial Virulence Determinants 1,” Annual Review of Immunology 14 (1996): 533–561.

[50] D. M. Monack, A. Mueller, and S. Falkow, “Persistent Bacterial Infections: The Interface of the Pathogen and the Host Immune System,” Nature Reviews Microbiology 2 (2004): 747–765.

[51] B. B. Finlay and G. McFadden, “Anti-Immunology: Evasion of the Host Immune System by Bacterial and Viral Pathogens,” Cell 124 (2006): 767–782.

[52] G. J. Nau, J. F. Richmond, A. Schlesinger, E. G. Jennings, E. S. Lander, and R. A. Young, “Human Macrophage Activation Programs Induced by Bacterial Pathogens,” Proceedings of the National Academy of Sciences of the United States of America 99 (2002): 1503–1508.

[53] M. Benoit, B. Desnues, and J.-L. Mege, “Macrophage Polarization in Bacterial Infections,” Journal of Immunology 181 (2008): 3733–3739.

[54] X. Zhang, Z. Zhang, Q. Shu, et al., “Copper Clusters: An Effective Antibacterial for Eradicating Multidrug-Resistant Bacterial Infection In Vitro and In Vivo,” Advanced Functional Materials 31 (2021): 2008720.

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2025 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.