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.

中文翻译：

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根皮素靶向多磷酸激酶 1 以减弱鲍曼不动杆菌在体外和体内的毒力和持久性


鲍曼不动杆菌 （A. baumannii） 以其毒力和持久性而闻名，尤其是在重症监护病房中。因此，考虑到耐药菌的出现，迫切需要治疗鲍曼不动杆菌感染的新策略和候选者。多磷酸激酶 1 （PPK1） 是细菌存活所必需的，因为它参与维持抗生素耐药性或耐受性、发病机制和逆境耐药性。本研究进行了与毒力和持久性相关的多种表型测定，根皮素显示可通过抑制 PPK1 活性减弱鲍曼不动杆菌的毒力和持久性。根皮素阻碍了鲍曼曲霉的活动能力，干扰了生物膜的形成，并降低了对氨苄青霉素、热和过氧化氢胁迫的抵抗力。还在小鼠肺炎感染模型中检查了治疗效果。分子模拟和定点诱变显示 ARG-22 、 MET-622 、 ASN-57 和 ARG-65 是根皮素对 PPK1 的作用位点。根皮素处理导致与鲍曼不动杆菌毒力和持久性相关的代谢途径发生变化，包括甘油磷脂代谢和脂肪酸生物合成。此外，根皮素在小鼠肺炎感染模型中减轻了体内肺炎损伤，表明根皮素是一种很有前途的化合物，可通过靶向 PPK1 来预防鲍曼不动杆菌感染耐药。