Phloretin Targets Polyphosphate Kinase 1 to Attenuate Acinetobacter baumannii Virulence and Persistence In Vitro and In Vivo
Hongfa Lv,
Shufang Li,
Jian Guan,
Peng Zhang,
Lingcong Kong,
Hongxia Ma,
Dan Li,
Xuming Deng,
Xiaodi Niu,
Jianfeng Wang
Affiliations
Hongfa Lv
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory for Zoonosis Research (Ministry of Education of the People's Republic of China), Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Shufang Li
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory for Zoonosis Research (Ministry of Education of the People's Republic of China), Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Jian Guan
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory for Zoonosis Research (Ministry of Education of the People's Republic of China), Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Peng Zhang
Department of Thoracic Surgery, the First Hospital of Jilin University, Changchun 130021, China
Lingcong Kong
College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
Hongxia Ma
College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
Dan Li
Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130021, China
Xuming Deng
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory for Zoonosis Research (Ministry of Education of the People's Republic of China), Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China
Xiaodi Niu
College of Food Science and Engineering, Jilin University, Changchun 130062, China; Corresponding authors.
Jianfeng Wang
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases & Key Laboratory for Zoonosis Research (Ministry of Education of the People's Republic of China), Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China; Corresponding authors.
Acinetobacter baumannii (A. baumannii) is well known for its virulence and persistence, particularly in intensive care units. Therefore, new strategies and candidates to treat A. baumannii infection are urgently needed considering the emergence of drug-resistant bacteria. Polyphosphate kinase 1 (PPK1) is required for bacterial survival as it is involved in maintaining antibiotic resistance or tolerance, pathogenesis, and adversity resistance. Multiple phenotypic assays related to virulence and persistence were performed in this study, and phloretin was shown to attenuate A. baumannii virulence and persistence by inhibiting PPK1 activity. Phloretin hampered mobility, interfered with biofilm formation and decreased resistance to ampicillin, heat, and hydrogen peroxide stress in A. baumannii. The therapeutic effect was also examined in a mouse pneumonia infection model. Molecular simulation and site-directed mutagenesis revealed that ARG-22, MET-622, ASN-57, and ARG-65 were the sites of phloretin action against PPK1. Phloretin treatment led to changes in metabolic pathways associated with A. baumannii virulence and persistence, including glycerophospholipid metabolism and fatty acid biosynthesis. Furthermore, phloretin alleviated pneumonic injury in a mouse pneumonia infection model in vivo, indicating that phloretin is a promising compound for preventing A. baumannii infection resistance by targeting PPK1.
