title: Inhibition of sortase A by chalcone prevents Listeria monocytogenes infection.
abstract: The critical role of sortase A in gram-positive bacterial pathogenicity makes this protein a good potential target for antimicrobial therapy. In this study, we report for the first time the crystal structure of Listeria monocytogenes sortase A and identify the active sites that mediate its transpeptidase activity. We also used a sortase A (SrtA) enzyme activity inhibition assay, simulation, and isothermal titration calorimetry analysis to discover that chalcone, an agent with little anti-L. monocytogenes activity, could significantly inhibit sortase A activity with an IC50 of 28.41 ± 5.34 μM by occupying the active site of SrtA. The addition of chalcone to a co-culture of L. monocytogenes and Caco-2 cells significantly inhibited bacterial entry into the cells and L. monocytogenes-mediated cytotoxicity. Additionally, chalcone treatment decreased the mortality of infected mice, the bacterial burden in target organs, and the pathological damage to L. monocytogenes-infected mice. In conclusion, these findings suggest that chalcone is a promising candidate for the development of treatment against L. monocytogenes infection.
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Hongen
authors.initials: H
authors.lastname: Li
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Niu
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN, United States.
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Gejin
authors.initials: G
authors.lastname: Lu
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Liu
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China. Electronic address: wjf927@jlu.edu.cn.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China. Electronic address: dengxm@jlu.edu.cn.
authors.forename: Xuming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000595:Amino Acid Sequence; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018938:Caco-2 Cells; D020134:Catalytic Domain; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008089:Listeria monocytogenes / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D008088:Listeriosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D047188:Chalcones; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases
keywords: Anti-infection; Chalcone; Listeria monocytogenes; Sortase A