Lipopolysaccharides (LPS, endotoxin) represent a major virulence factor of
Gram-negative bacteria, which can cause septic shock in mammals, including
man. The lipid anchor of LPS to the bacterial outer membrane, lipid A, exhi
bits a peculiar chemical structure, harbours the 'endotoxic principle' of L
PS and is also responsible for the expression of pathophysiological effects
. Chemically modified lipid A can be endotoxically inactive, but may expres
s strong antagonistic activity against endotoxically active LPS. By applyin
g orientation measurements with attenuated total reflectance (ATR) infrared
spectroscopy on hydrated lipid A samples, we show here that these differen
t biological activities are directly correlated to the intrinsic conformati
on of lipid A. Bisphosphoryl-hexaacyl lipid A molecules with an asymmetric
(4/2) distribution of the acyl chains linked to the diglucosamine backbone
have a large tilt angle (> 45 degrees) of the diglucosamine backbone with r
espect to the membrane surface, a conical molecular shape (larger cross-sec
tion of the hydrophobic than the hydrophilic moiety), and are endotoxically
highly active. Monophosphoryl hexaacyl lipid A has a smaller tilt angle, a
nd the conical shape is less expressed in favour of a more cylindrical shap
e. This correlates with decreasing endotoxic activity. Penta- and tetraacyl
lipid A or hexaacyl lipid A with a symmetric acyl chain distribution (3/3)
have a small tilt angle (< 25 degrees) and a cylindrical shape and are end
otoxically inactive, but may be antagonistic.