title: Baicalin protects mice from Staphylococcus aureus pneumonia via inhibition of the cytolytic activity of α-hemolysin.
abstract: α-Hemolysin (Hla) is a self-assembling, channel-forming toxin that is secreted by Staphylococcus aureus and is central to the pathogenesis of pulmonary, intraperitoneal, intramammary, and corneal infections in animal models. In this study, we report that baicalin (BAI), a natural compound that lacks anti-S. aureus activity, could inhibit the hemolytic activity of Hla. Using molecular dynamics simulations and mutagenesis assays, we further demonstrate that BAI binds to the binding sites of Y148, P151, and F153 in the Hla. This binding interaction inhibits heptamer formation. Furthermore, when added to S. aureus cultures, BAI prevents Hla-mediated human alveolar epithelial (A549) cell injury. In vivo studies further demonstrated that BAI protects mice from S. aureus pneumonia. These findings indicate that BAI hinders the cell lysis activity of Hla through a novel mechanism of interrupting the formation of heptamer, which may lead to the development of novel therapeutics that aim against S. aureus Hla.
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, China.
authors.forename: Jiazhang
authors.initials: J
authors.lastname: Qiu
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Niu
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.forename: Dacheng
authors.initials: D
authors.lastname: Wang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.forename: Hongen
authors.initials: H
authors.lastname: Li
authors.forename: Mingjing
authors.initials: M
authors.lastname: Luo
authors.forename: Shentao
authors.initials: S
authors.lastname: Li
authors.forename: Haihua
authors.initials: H
authors.lastname: Feng
authors.forename: Xuming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011023:Pneumonia, Staphylococcal / Q000517:prevention & control*; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D001427:Bacterial Toxins; D005419:Flavonoids; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin; C038044:baicalin