Lipopolysaccharides (LPS) are highly variable molecules, with modifications to Lipid A, core sugars, and O-antigen enabling bacterial cells to adapt to environmental stresses, evade immunity, and resist antibiotics . These modifications are critical in conferring resistance also to endogenous AMPs while modulating the activation of Toll-like receptor 4 (TLR4, also CD284). Gram-negative bacteria suppress TLR4 activation by altering Lipid A structure to delay or evade innate immune responses while reinforcing LPS-LPS interactions with cationic moieties to prevent AMP activity. H. pylori provides a prime example of this dual strategy, thriving in the harsh gastric mucosa environment. To survive, H. pylori extensively modifies its LPS: phosphorylation and the O-antigen sequence are optimized for survival in the stomach, Lipid A acylation is reduced from six to four chains, thereby reducing TLR4 activation , mimicking the TLR4 antagonist Eritoran (TLR4-Eritoran complex at PDB ID 2z65 ). As illustrated in Figure the number of acyl chains induces different Lipid A may be tetra-acylated (e.g., H. pylori), hexa-acylated (E. coli, P. aeruginosa, N. gonorrhoeae), or even hepta-or octa-acylated (V. cholerae). It can be further modified with groups such as phosphate-ethanolamine (pEtN), 4-amino-4-deoxy-L-arabinose (L-Ara4N), or (di)glycyl moieties. In H. pylori, one sugar of Lipid A may also be dephosphorylated. Color scheme: Glucosamine I and its attached acyl chains are shown in cyan, Glucosamine II (linked to the sugar core) and its acyl chains in magenta, and additional substituent groups (pEtN, L-Ara4N, di-Glycyl) in green. conformational changes in TLR4 , resulting in a positive correlation between the number of acyl chains in . These changes also neutralize Lipid A's phosphate groups via pEtN addition (by EptA) and phosphate removal (by LpxG), rendering the outer membrane highly resistant to cationic AMPs and antibiotics like polymyxins . The phosphate removal, in particular, significantly raises polymyxin B's minimum inhibitory concentration (MIC), a decisive feature for host colonization . Furthermore, H. pylori expresses Lewis O-antigens (sugar sequences mimicking blood groups antigens), sugar sequences mimicking human blood group antigens, enabling immune evasion . Other species employ similar strategies. pEtN or ppEtN modifications to Lipid A and inner core Heptose sugars stabilize LPS-LPS and Ca 2+ -LPS interactions, forming a dense steric and electrostatic barrier against . These modifications render LPS-AMP interactions energetically unfavorable, further enhancing resistance. Divalent cations, essential for LPS stability under normal conditions [284], synergize with pEtN/ppEtN modifications to strengthen the LPS-LPS interactions.