title: Curcumin protects mice from Staphylococcus aureus pneumonia by interfering with the self-assembly process of α-hemolysin.
abstract: α-hemolysin (Hla) is a self-assembling extracellular protein secreted as a soluble monomer by most Staphylococcus aureus strains and is an essential virulence factor for the pathogenesis of various S. aureus infections. Here, we show that curcumin (CUR), a natural compound with weak anti-S. aureus activity, can inhibit the hemolysis induced by Hla. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were further employed for the Hla-CUR complex to determine the mechanism of such inhibition. The analysis of this combined approach indicated that the direct binding CUR to Hla blocks the conformational transition of Hla from the monomer to the oligomer, leading to an inhibition of Hla hemolytic activity. We also found that the addition of CUR significantly attenuated Hla-mediated injury of human alveolar cell (A549) co-cultured with S. aureus. The in vivo data further demonstrated that treatment with CUR protects mice from pneumonia caused by S. aureus, including methicillin-resistant strains (MRSA). These findings suggest that CUR inhibits the pore-forming activity of Hla through a novel mechanism, which would pave the way for the development of new and more effective antibacterial agents to combat S. aureus pneumonia.
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, and Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, and Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, and Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, and Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Xuming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, and Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, and Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Niu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D005260:Female; D006460:Hemolysin Proteins / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects; D016106:Methicillin Resistance / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy*; D020011:Protective Agents / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D020011:Protective Agents; D037521:Virulence Factors; D003474:Curcumin