Phloretin AttenuatesListeria monocytogenesVirulence BothIn vitroandIn vivoby Simultaneously Targeting Listeriolysin O and Sortase A.
The critical roles of sortase A (SrtA) and listeriolysin O (LLO) inListeria monocytogenespathogenicity render these two virulence factors as ideal targets for the development of anti-virulence agents againstL. monocytogenesinfection. Additionally, the structures of SrtA and LLO are highly conserved among the members of sortase enzyme family and cholesterol dependent toxin family. Here, phloretin, a natural polyphenolic compound derived from apples and pears that has little anti-L. monocytogenesactivity, was identified to simultaneously inhibit LLO expression and neutralize SrtA catalytic activity. Phloretin neutralized SrtA activity by causing a conformational change in the protein's active pocket, which prevented engagement with its substrate. Treatment with phloretin simultaneously reducedL. monocytogenesinvasion into host cells and blocked the escape of vacuole-entrappedL. monocytogenesinto cytoplasm. Further,L. monocytogenes-infected mice that received phloretin showed lower mortality, decreased bacterial burden and reduced pathological injury. Our results demonstrate that phloretin is a promising anti-infective therapeutic for infections caused byL. monocytogenesdue to its simultaneous targeting of SrtA and LLO, which may result in fewer side effects than those caused by other antibiotics.
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Jianfeng
J
Wang
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Bowen
B
Liu
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Zihao
Z
Teng
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Xuan
X
Zhou
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Xiyan
X
Wang
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Bing
B
Zhang
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Gejin
G
Lu
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Xiaodi
X
Niu
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Yongjun
Y
Yang
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Xuming
X
Deng
D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000378:metabolism*; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D018938:Caco-2 Cells; D002470:Cell Survival; D003546:Cysteine Endopeptidases; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D004847:Epithelial Cells / Q000382:microbiology / Q000502:physiology; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008089:Listeria monocytogenes / Q000187:drug effects* / Q000472:pathogenicity*; D008088:Listeriosis / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D010693:Phloretin / Q000008:administration & dosage / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome; D014774:Virulence
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases; C038705:hlyA protein, Listeria monocytogenes; D010693:Phloretin
Listeria monocytogenes; anti-infective therapy; listeriolysin O; phloretin; sortase A