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3‐deoxy‐ d ‐manno‐octulosonic acid‐lipid A (Kdo 2 ‐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  Kdo 2 ‐lipid A has been elucidated and the nine enzymes of the pathway are shared by most Gram‐negative bacteria, indicating conserved Kdo 2 ‐lipid A structure across different species. Yet many bacteria can modify the structure of their Kdo 2 ‐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 Kdo 2 ‐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 Kdo 2 ‐lipid A or correspondingly engineered live bacteria as vaccines and adjuvants. Kdo 2 ‐lipid A/ TLR4  antagonists can also be applied in anti‐inflammatory interventions. This review summarizes recent knowledge on both the fundamental processes of Kdo 2 ‐lipid A biosynthesis, structural modification and immune stimulation, and applied research on pharmacological exploitations of these processes for therapeutic development.

Kdo 2 ‐lipid A: structural diversity and impact on immunopharmacology