Discovery of Kaempferol, a Novel ADAM10 Inhibitor, as a Potential Treatment for Staphylococcus aureus Infection
Tingting Wang,
Jianfeng Wang,
Xiangzhu Xu,
Fan Jiang,
Hongfa Lv,
Qinghui Qi,
Can Zhang,
Qianghua Lv,
Xuming Deng
Affiliations
Tingting Wang
Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases & Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory for Zoonotic Diseases, The First Hospital of Jilin University, Changchun 130021, China; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Jianfeng Wang
Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases & Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory for Zoonotic Diseases, The First Hospital of Jilin University, Changchun 130021, China; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China; Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
Xiangzhu Xu
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Fan Jiang
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Hongfa Lv
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Qinghui Qi
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Can Zhang
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Qianghua Lv
Key Laboratory of Livestock and Poultry Multi-omics of MARA & Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan 250100, China; Corresponding authors.
Xuming Deng
Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases & Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory for Zoonotic Diseases, The First Hospital of Jilin University, Changchun 130021, China; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China; Corresponding authors.
Host-directed therapy (HDT) is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus (S. aureus) infection. Functioning as the indispensable specific cellular receptor for α-toxin (Hla), a-disintegrin and metalloproteinase 10 (ADAM10) is exploited to accelerate S. aureus infection through diverse mechanisms. The extraordinary contribution of ADAM10 to S. aureus pathogenesis renders it an attractive HDT target for combating S. aureus infection. Our study is the first to demonstrate the indispensable role of ADAM10 in S. aureus-induced necroptosis, and it enhances our knowledge of the role of ADAM10 in S. aureus infection. Using a fluorogenic substrate assay, we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S. aureus infection by suppressing Hla-mediated barrier disruption and necroptosis. Collectively, our work presents a novel host-directed therapeutic strategy for using the promising candidate kaempferol to treat S. aureus infection and other diseases relevant to the disordered upregulation of ADAM10.
