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, Jilin, 130021, China.
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.
Microb Cell Fact. 2024 Oct 8;23(1):269. doi: 10.1186/s12934-024-02540-9.
Inorganic polyphosphate (polyP)-targeted polyphosphate kinase 1 (PPK1) has attracted much attention by virtue of its importance in bacterial pathogenicity and persistence, as well as its exclusive presence in microorganisms. However, only very few drugs have been found to be efficacious in inhibiting the Acinetobacter baumannii (A. baumannii) PPK1 protein.
In this study, we identified Scutellarein (Scu), a potent PPK1 inhibitor that could significantly influence PPK1-regulated motility, biofilm formation, and bacterial persistence, which was further validated by the results of transcriptome analysis. Mechanistic explorations revealed that Scu achieved its enzyme inhibitory activity predominantly through direct engagement with the active center of PPK1. Moreover, the survival rate of Galleria mellonella larvae was increased by about 35% with 20 mg/kg of Scu treatment. The remarkable therapeutic benefits of Scu were also observed in the mouse pneumonia model, shown mainly by reduced bacterial colonization, pathological lesions, and inflammatory factors.
Our results revealed that Scu could attenuate the pathogenicity and persistence of A. baumannii by interfering with its important kinase PPK1.
无机多聚磷酸盐（polyP）靶向多聚磷酸盐激酶 1（PPK1）因其在细菌致病性和持久性中的重要性以及其在微生物中的独特存在而受到广泛关注。然而，仅有极少数药物被发现能够有效抑制鲍曼不动杆菌（A.baumannii）的 PPK1 蛋白。
在本研究中，我们鉴定了 Scutellarein（Scu），一种有效的 PPK1 抑制剂，它可以显著影响 PPK1 调节的运动性、生物膜形成和细菌持久性，转录组分析的结果进一步验证了这一点。机制探索表明，Scu 主要通过与 PPK1 的活性中心直接结合来发挥其酶抑制活性。此外，用 20mg/kg 的 Scu 处理后，大蜡螟幼虫的存活率提高了约 35%。Scu 在小鼠肺炎模型中也表现出显著的治疗益处，主要表现为细菌定植、病理损伤和炎症因子减少。
我们的结果表明，Scu 可以通过干扰其重要的激酶 PPK1 来减轻鲍曼不动杆菌的致病性和持久性。
