3-deoxy-d-manno-octulosonic acid-lipid A (Kdo2 -lipid A) is the essential component of lipopolysaccharide in most Gram-negative bacteria and the minimal structural component to sustain bacterial viability. It serves as the active component of lipopolysaccharide to stimulate potent host immune responses through the complex of Toll-like-receptor 4 (TLR4) and myeloid differentiation protein 2. The entire biosynthetic pathway of Escherichia coli Kdo2 -lipid A has been elucidated and the nine enzymes of the pathway are shared by most Gram-negative bacteria, indicating conserved Kdo2 -lipid A structure across different species. Yet many bacteria can modify the structure of their Kdo2 -lipid A which serves as a strategy to modulate bacterial virulence and adapt to different growth environments as well as to avoid recognition by the mammalian innate immune systems. Key enzymes and receptors involved in Kdo2 -lipid A biosynthesis, structural modification and its interaction with the TLR4 pathway represent a clear opportunity for immunopharmacological exploitation. These include the development of novel antibiotics targeting key biosynthetic enzymes and utilization of structurally modified Kdo2 -lipid A or correspondingly engineered live bacteria as vaccines and adjuvants. Kdo2 -lipid A/TLR4 antagonists can also be applied in anti-inflammatory interventions. This review summarizes recent knowledge on both the fundamental processes of Kdo2 -lipid A biosynthesis, structural modification and immune stimulation, and applied research on pharmacological exploitations of these processes for therapeutic development.

中文翻译：

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Kdo2 -lipid A：结构多样性和对免疫药理学的影响。

3-脱氧-d-甘露糖-辛糖酸-脂质 A (Kdo2 -lipid A) 是大多数革兰氏阴性菌中脂多糖的主要成分，也是维持细菌活力的最小结构成分。它作为脂多糖的活性成分，通过 Toll 样受体 4 (TLR4) 和髓样分化蛋白 2 的复合物刺激有效的宿主免疫反应。大多数革兰氏阴性细菌共享该途径的酶，表明不同物种之间存在保守的 Kdo2 -lipid A 结构。然而，许多细菌可以修改它们的 Kdo2-脂质 A 的结构，这是调节细菌毒力和适应不同生长环境以及避免被哺乳动物先天免疫系统识别的策略。参与 Kdo2 -lipid A 生物合成、结构修饰及其与 TLR4 途径相互作用的关键酶和受体代表了免疫药理学开发的明确机会。这些包括开发针对关键生物合成酶的新型抗生素，以及利用结构修饰的 Kdo2-脂质 A 或相应工程化的活细菌作为疫苗和佐剂。Kdo2-lipid A/TLR4 拮抗剂也可用于抗炎干预。本综述总结了 Kdo2-脂质 A 生物合成的基本过程的最新知识，