{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:16:32Z","timestamp":1775279792591,"version":"3.50.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>In previous research, antibacterial photodynamic therapy using lysine-porphyrin conjugate LD<jats:sub>4<\/jats:sub> effectively inactivated methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli; however, it exhibited limited activity against Candida albicans and Mycobacterium tuberculosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To address this limitation, we developed a synergistic antibacterial strategy by combining LD<jats:sub>4<\/jats:sub> with Cu<jats:sup>2+<\/jats:sup> or Zn<jats:sup>2+<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Synergy was confirmed via minimum inhibitory concentration and fractional inhibitory concentration index analyses, demonstrating 16- to 64-fold enhanced antibacterial efficacy compared to LD<jats:sub>4<\/jats:sub> alone. Mechanistic studies revealed divergent pathways for LD<jats:sub>4<\/jats:sub> + Cu<jats:sup>2+<\/jats:sup> and LD<jats:sub>4<\/jats:sub> + Zn<jats:sup>2+<\/jats:sup>: Zn<jats:sup>2+<\/jats:sup> increased the reactive oxygen species yield and promoted LD4 uptake by pathogens, while LD<jats:sub>4<\/jats:sub> + Cu<jats:sup>2+<\/jats:sup> induced oxidative damage to cell walls and membranes in darkness, with light exposure exacerbating structural damage. Cytotoxicity assessments confirmed low toxicity, with &amp;gt;90% survival of normal cells at bactericidal concentrations. Fluorescence and infrared spectroscopy characterized metal-LD<jats:sub>4<\/jats:sub> complexes, showing stabilization through interactions between amino and pyrrolic imino groups of LD<jats:sub>4<\/jats:sub> and metal ions, which promoted non-radiative transitions and fluorescence quenching. Both combinations caused significant bacterial membrane disruption and growth suppression. Notably, cytotoxicity exhibited a biphasic dose-response linked to metal-LD<jats:sub>4<\/jats:sub> complexation-dependent particle size changes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This study elucidated the enhanced antimicrobial mechanisms and safety of LD<jats:sub>4<\/jats:sub>-metal ion combinations. The findings resolve the limitations of LD<jats:sub>4<\/jats:sub> while providing a theoretical framework for developing novel therapies against fungal and mycobacterial infections.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1626193","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T05:37:24Z","timestamp":1753940244000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Synergistic antibacterial photodynamic therapy of lysine-porphyrin conjugate and metal ions combination against Candida albicans and Mycobacterium tuberculosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Xueming","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhonghua","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingxuan","family":"Chi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lixia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junping","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianjun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1080\/1040841X.2024.2313024","article-title":"Antibiotic resistance: a global crisis, problems and solutions","volume":"50","author":"Aggarwal","year":"2024","journal-title":"Crit. 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