AGONISTIC AND ANTAGONISTIC ACTIVITIES OF BACTERIALLY DERIVED RHODOBACTER-SPHAEROIDES LIPID-A - COMPARISON WITH ACTIVITIES OF SYNTHETIC MATERIAL OF THE PROPOSED STRUCTURE AND ANALOGS
Jr. Rose et al., AGONISTIC AND ANTAGONISTIC ACTIVITIES OF BACTERIALLY DERIVED RHODOBACTER-SPHAEROIDES LIPID-A - COMPARISON WITH ACTIVITIES OF SYNTHETIC MATERIAL OF THE PROPOSED STRUCTURE AND ANALOGS, Infection and immunity, 63(3), 1995, pp. 833-839
Lipid A from the photosynthetic bacterium Rhodobacter sphaeroides (RSL
A) has been previously shown to antagonize many of the effects of endo
toxins from more pathogenic gram-negative bacteria. We have reported o
n the synthesis of the proposed structure of RSLA and determined that
bacterially derived RSLA is not identical to its proposed structure (W
.J. Christ, P.D. McGuinness, O. Asano, Y. Wang, M. A. Mullarkey, M. Pe
rez, L.D. Hawkins, T.A. Blythe, G.R Dubuc, and A.L. Robidoux, J. Am. C
hem. Sec. 116:3637-3638, 1994). Here we report results of analyzing th
e antagonistic and agonistic activities of bacterially derived RSLA in
comparison with the activities of chemically synthesized material of
the; proposed structure of RSLA and analogs. Results indicated that al
l compounds were approximately equally potent at inhibiting endotoxin-
induced release of tumor necrosis factor alpha from human monocytes an
d human whole blood as well as endotoxin-induced generation of nitric:
oxide in murine macrophages. In addition, all compounds were of equiv
alent potencies at inhibiting the binding of I-125-labelled lipopolysa
ccharide derivatized with 2-(p-azido-salicylamido) ethyl-1-3'-dithiopr
opionate to murine macrophages. Higher concentrations of bacterially d
erived RSLA (10 to 100 mu M) were agonistic in human and murine assays
, In gamma interferon-treated murine macrophages, agonism was exhibite
d at concentrations as low as 100 nM. In contrast, all synthetic mater
ials were either dramatically less agonistic or devoid of agonistic ac
tivity when tested at concentrations as high as 100 mu M. It is possib
le either that bacterially derived RSLA contains a small amount of a h
ighly agonistic impurity or that the agonistic activity of RSLA is int
rinsic to its molecular structure. In either case, these biological re
sults support our previous report concluding that biologically derived
RSLA is not identical to synthetic material of its proposed structure
.