title: Fisetin inhibits Listeria monocytogenes virulence by interfering with the oligomerization of listeriolysin O.
abstract: Listeriolysin O (LLO), an essential virulence determinant of Listeria monocytogenes, is a pore-forming toxin whose primary function is to facilitate cytosolic bacterial replication by breaching the phagosomal membranes, which is critical for the pathogen to evade host immune recognition. The critical role of LLO in the virulence of L. monocytogenes renders it an ideal target for designing novel antivirulence therapeutics. We found that fisetin, a natural flavonoid without antimicrobial activity, is a potent antagonist of LLO-mediated hemolysis. Fisetin effectively inhibits L. monocytogenes infection in both tissue culture and animal infection models. Molecular modeling and mutational analysis revealed that fisetin directly engages loop 2 and loop 3 of LLO, leading to the blockage of cholesterol binding and the reduction of its oligomerization, thus inhibiting its hemolytic activity. Our results establish fisetin as an effective antitoxin agent for LLO, which can be further developed into novel therapeutics against infections caused by L. monocytogenes.
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Jiazhang
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Hongshu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Shui
authors.initials: S
authors.lastname: Liu
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Haihua
authors.initials: H
authors.lastname: Feng
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Food Quality and Safety, Jilin University, Changchun, China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Niu
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine.
authors.forename: Xuming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D044948:Flavonols; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D014774:Virulence
chemical_list: D001427:Bacterial Toxins; D005419:Flavonoids; D044948:Flavonols; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; C017875:fisetin; C038705:hlyA protein, Listeria monocytogenes
keywords: anti-virulence; infection; molecular modeling; toxin