title: Rapid killing of bacteria by a new type of photosensitizer.
abstract: Photodynamic antimicrobial chemotherapy (PACT) uses non-traditional mechanisms (free radicals) and is a highly advocated method with promise of inactivating drug-resistance bacteria for local infections. However, there is no related drug used in clinical practice yet. Therefore, new photosensitizers for PACT are under active development. Here, we report the synthesis of a series of photosensitizers with variable positive charges (ZnPc(TAP)4n+, n = 0, 4, 8, 12) and their inactivation against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. The binding kinetics of ZnPc(TAP)4n+to bacteria were measured by flow cytometer. Reactive oxygen species (ROS) generation mechanism of the photosensitizers was studied. The toxicity of these compounds to human blood cells was also evaluated. These compounds showed negligible toxicity against human erythocytes but potent bactericidal effects. The compound with 8 positive charges, ZnPc(TAP)48+, turned out to have the strongest antibacterial effect among this series of compounds, giving IC50value of 59 nM at a light dosage of 5 J/cm2toward E. coli. For a multi-resistant E. coli strain, ZnPc(TAP)48+decreased the bacteria load by 1000-fold at a concentration of 1 μM. Interestingly, ZnPc(TAP)412+, instead of ZnPc(TAP)48+, exhibited the highest amount of binding to bacteria. Flow cytometry studies showed that all PSs have fast binding onto bacteria, reaching saturated binding within 5 min. Mechanistically, ZnPc(TAP)412+generated ROS primarily via Type I mechanism, while ZnPc(TAP)44+or ZnPc(TAP)48+created ROS by both type I and type II mechanisms. ZnPc(TAP)4n+are highly potent, rapid-acting and non-toxic photosensitizers capable of inactivating bacteria.
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, 266042, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China.
authors.forename: Jincan
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China.
authors.forename: Linrong
authors.initials: L
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China.|Department of Chemistry, COMSATS Institute of Information Technology (CIIT), Abbottabad, KPK, 22060, Pakistan.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China. mhuang@fjirsm.ac.cn.|College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350118, China. mhuang@fjirsm.ac.cn.
authors.forename: Mingdong
authors.initials: M
authors.lastname: Huang
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D058491:Bacterial Load / Q000187:drug effects / Q000528:radiation effects; D024881:Drug Resistance, Bacterial; D004912:Erythrocytes / Q000187:drug effects / Q000528:radiation effects; D004926:Escherichia coli / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D020128:Inhibitory Concentration 50; D054833:Isoindoles; D007700:Kinetics; D008027:Light; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000528:radiation effects
chemical_list: D000900:Anti-Bacterial Agents; D007211:Indoles; D054833:Isoindoles; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; C013647:phthalocyanine
keywords: Mechanistic study; Photodynamic antimicrobial chemotherapy (PACT); Photosensitizer; Phthalocyanine; ROS measurement