close

Вход

Забыли?

вход по аккаунту

?

Endotoxin Antagonists Possible Candidates for the Treatment of Gram-Negative Sepsis.

код для вставкиСкачать
HIGHLIGHTS
Endotoxin Antagonists: Possible Candidates for the Treatment
of Gram-Negative Sepsis**
Otto Holst”
The endotoxins [lipopolysaccharides (LPS)] of Gram-negative bacteria are amphiphilic macromolecules located in the outer membrane of the cell wall.[’. ’] LPS are essential for bacterial
survival; they augment the rigidity of the cell wall and protect
bacteria from bile acids, gut enzymes, and defense mechanisms
of the host, and from antibiotics. In higher animals and humans,
however, endotoxins exhibit a variety of pathophysiological effects. Even in minor amounts they may invoke a sepsis which.
accompanied by hypotension and multiple organ failure, leads
to septic shock that is the major cause of death in intensive care
units worldwide. Moreover, LPS are antigens and thus involved
in the process of recognition of bacteria and the host’s defense.
The biological activities of LPS and their clinical relevance are
main impulses for tremendous international research on the
structure and function of LPS and possible approaches to sepsis
therapy.
LPS of all Gram-negative bacteria share a common architecture (Scheme I).[*] They consist of a lipidic portion. the
lipid A,[31which anchors the molecule in the outer membrane
0-Specific
Chain
are stimulated to synthesize and release distinct mediator substances such as tumor necrosis factor-a (TNF-a) and the interleukins (11) 1,6, and S.[’] Overproduction of mediators results in
the pathophysiological effects of endotoxins. The initialization
of this cascade does not require a complete LPS molecule. As
postulated in the 1950s and verified in the 1 9 8 0 ~ [ ~ in
, ’ ]various
biological experiments using natural isolates and synthetic
Escherichia coli lipid A (Scheme 2), lipid A represents the toxic
principle of LPS.
0
II
’p
‘OH
HO
Outer
Core
Scheme 1 . General structure of bacterial LPS.
and which is linked to a more or less complex carbohydrate
chain. In various bacterial families (e.g. Enterohacteriuceae,
Vihrionaceae) this is an oligosaccharide unit with up to 15
monosaccharides (the core region), which is substituted with a
polysaccharide of repeating units (the 0-antigen, S-form
LPS).[41A second type of LPS. which was first identified in
mutants carrying a defect in the gene cluster responsible for
0-antigen biosynthesis (cfh), consists only of lipid A and the
core region (R-form LPS). Later, this type of LPS was also
found in bacteria without known genetic defects. for example. in
Bordetella pertussis (whooping cough) and Neisseria gonorrhoeae (gonorrhea).
During infection, LPS are liberated from bacteria. for example after cell death. These LPS react with various serum
components. a prominent member of which is the “lipopolysaccharide binding protein” (LBP). LPS complex with LBP
and may then be bound to a receptor (CD14) of macrophages,
which through a not yet elucidated signal transduction pathway
[*I
Priv.-Dor. Dr 0. Holsr
Forschungsinstitut Borstel
lnstitut fur Experimentelle Biologic und Medirin
Parkallee 22. D-23845 Borstel (Germany)
Telefax: Inr. code +(4537) 10419
[**I I thank
Dr. U. Zihringer for help in preparinp the schemes and Professor H.
Brade for critical reading of the manuscript.
Scheme 2. Structure of lipid A from E. i d r . The circled numbers refer to thc length
of the carbon chain
Today, the mortality rate of Gram-negative sepsis is still as
high as 60%, owing to an increasing distribution of antibioticresistent bacteria in hospitals. Additionally. LPS are liberated
from bacteria by antibiotics. New strategies to avoid or treat
Gram-negative sepsis could affect different stages of the endotoxin cascade: the LPS, the interaction of LPS with serum components/cell receptors, or the production and secretion of mediators. Besides efforts to obtain cross-reactive and -protective
antibodies in particular against lipid A, an inhibitor of the
TNF-a synthesis was identified which protects mice against the
lethal effects of endotoxin. One monoclonal antibody (HA-1A)
was applied clinically; however, its distribution has been
stopped in the meantime, since it proved to be a failure.
In my opinion recent investigations concerning the effects of
nontoxic endotoxin antagonists are also very important. These
are structural analogues of lipid A. some of which are shown in
Scheme 3. One example is tetraacyl lipid A (A) (precursor Ia),
a precursor in lipid A biosynthesis which has also been synthesized chemically (Compound 406).[’. 91 As shown by different
research groups, precursor I a inhibits the LPS-induced specific
mRNA production for monokines in human macrophages.
Comparison of investigations using different structural analogues revealed that the effectiveness of these disaccharide an-
HIGHLIGHTS
A
B
\
D
C
Scheme 3 . Structures oT precursor l a ( A ) , lipid A from R. .spburroides (B), lipid A from R. ~~upsu/u~u.s
(C), and E5531 ( D ) .
tagonists depends on their acylation and phosphorylation pattern. Tetraacylated and bisphosphorylated precursor I a is one
of the most effective inhibitors known to date. In macrophages
and monocytes, the mechanism of the inhibition is based on
competitive binding of the antagonist to CD14. However, since
precursor I a exhibits agonistic activities in vitro and in vivo in
mice (but not in humans), it is not possible to test this substance
in a murine sepsis model.
Other antagonists are the nontoxic lipid A of Rhodohricter
splicreroiclr~s(B) and R. capsulatus ( C ) (Scheme 3).['0-'51 The
lipid A of R . splzurroides (B) was also chemically
A spectroscopic analysis identified differences with the structure
of the natural isolate. most likely in the fatty acids. The authors
thus suggested that the published structure of the isolated
lipid A is not correct. However, the discrepancy has not yet been
finally clarified. Recently, the synthesis of a structural analogue
(E5531, D in Scheme 3) of the lipid A from R. capsulatus was
described along with a broad characterization of its toxic and
antagonistic properties." Since the chemically synthesized R.
ccip.vuln/u.s lipid A ( C ) appeared to be unstable during storage
(hydrolytic cleavage of the acyl groups at C-3 and C-3' of the
glucosamine disaccharide) and, thus, did not fulfill an important
prerequisite of a drug. i t was necessary to synthesize a stable
derivative thereof. This was possible by introducing ether substituents at positions C-3 and C-3'. Just as fascinating as the
chemical synthesis are the results of the biological in vitro and
in vivo experiments using E5531 (D). First of all, the LPS-induced monokine production in human monocytes and whole
blood was inhibited by E5531. Notably, and in contrast to precursor I a (A), E5531 (D) did not show any agonistic activity in
either human or murine cells. Therefore, murine in vivo models
could be established. It was shown that the LPS-induced increase in the TNF-c( concentration in plasma and the 100%
mortality rate of the animals could be negated by coinjection of
E5531 (D). Even more important is the establishment of a
murine infection model. in which the animals can be protected
from experimental E. coli peritonitis by combined injection of
E5531 and a j-lactam antibiotic. This was not possible by injection ofeither E5531 or the antibiotic alone, and in the latter case
it was found that the antibiotic killed the bacteria but also liberated higher amounts of LPS. This infection model seems to
represent important processes of human sepsis and may thus be
an essential instrument in future in vivo investigations. Owing to
its favorable biological properties, E5531 (D) has already been
tested in a clinical phase I study; it did not show agonistic activity and decreased dose-dependant endotoxic LPS-effects, for
example the amount of released cytokines.
The results obtained to date indicate that nontoxic structural
analogues of lipid A such as precursor I a and E5531 are potent
endotoxin antagonists in vitro and, partially, also in vivo. Most
HIGHLIGHTS
191 S. Kusumoto in ref. [4a], p. X I .
[lo] N. Qureshi. K. Takayama, R. Kurtz, I n f i c t . hnmun. 1991. 59. 441 -444.
promising is E5531, a compound that may lead to an important
progress in the treatment of Gram-negative sepsis.
German version: Angew. Chein. 1995. 107. 2154 2156
Keywords: drugs endotoxins . lipopolysaccharides . medicinal
chemistry
[ I ] B. Lugtenberg, L van Alphen. Biodiim. Biopliw. .4crfi 1983. 737, 51 115.
[2] E. T. Rictschel. H. Brade. Sci. A m . 1992. 267. 54-61.
[3] U . Ziihringer. B. Lmdner, E. T. Rieischel, A&. Curhokjdr. Chrrii. Bioch~m.
1994. SO. 211 -276.
Vol. 1 (Eds.: D. C. Morrison, J. L.
[4] a) Bacreriul Endo/o.ric Lipopolj.~ucc.liuride.~,
Ryan), CRC, Boca Raton. FL. 1992; b) 0. Holst, H . Brdde in ref. [4a]. p. 135.
[ 5 ] E. T. Rietschel, H. Brade, 0. Holst, L. Brade, S. Muller-Loennies, U. Mamat,
U.Zihringer. E Beckinann, U. Seydel. K. Brandenburg, A. J. Ulmer. T. Mattern. H. Heine, J. Schletter, S. Hauschildt, H. Loppnow, H.-D. Flad. U. F.
Schdde. E Di Padova. R. R. Schumann. Curr. Tnp. Microhiol. ~ri~munol..
unpublished.
[6] 0. Westphal. 0. LuderitL. Angrw. Cliein. 1954. 66. 407-417.
[7] H. Brade. L. Brade. E. T. Rietschel. Zhl. Bukr. F/vg. A 1988, 268, 151-179.
[XI C . R . H. Raetr in ref. [4a], p. 67.
-
[ l l ] H. Loppnow, E. T. Rietschel. H. Brade, U . Schonbeck, P. Libby, M.-H. Wang,
H. Heine, W. Feist, 1. Diirrbaum-Landmann, M. Ernst, E. Brandt, E. GrageGriebenow, A. J. Ulmer, S. Campos-Portuguez, U. Schade, T. Kirikae. S. Kusumoto, J. Krauss, H. Mayer, H.-D. Flat in Buttrriul Endo/o.xin: Rivqniriuri
mid Elfcctor Mechanrsms (Eds.: J. Levin. C . R. Alving. R. S. Munford. P. L.
Stiitr). Elsevier, Amsterdam. 1993, p. 337.
[I21 P. V. Salimath, J. Weckesser, W. Strittmatter, H . Mayer, Euur..J. Biochivi?. 1983,
136. 195-200.
[13] N . Qureshi, J. P. Honovich. H. Hara, R. J. Cotter, K. Tdkaydma, J. B i d . C'hem.
1988. 263. 5502-5504.
[14] T. Merkofer. A. Neszmelyi. H . Mayer. Workshop Endoro.yini, und E.wro.\-ine oh
hukrerielh Porh(~g,jnirii/.~f~ik~uren,
1995. Forschungsinstitut Borstel, P 1.3.
[I51 J. H. Krauss. U. Seydel. J. Weckesser. H. Mayer, Eur. J. Biothrm. 1989. INO.
519-526.
[I61 W. J. Christ. P. D. McGuinness. 0. Asano. Y. Wang, M. A. Mullarkey, M.
Perez, L. D. Hawkins. T. A. Blyihe, G. R. Dubuc, A. L. Robidoux, J. Am.
Cliiw. Soc. 1994, 116. 363773638,
[I71 W. J. Christ. 0 . Asano. A. L. Robidoux. M. Perez. Y. Wang, G . R. Dubuc.
W. E. Gavin. L. D . Hawkins, P. D. McGuinness. M. A. Mullarkey. M. D.
Lewis, Y. Kishi. T. Kawata, J. R. Bristol. J. R. Rose. D. P. Rossignol. S.
Kohayashi. I. Hishinuma. A. Kimura. N. Asakawa, K. Katayama, I. Yamatsu.
Scienw 1995. 26X. X0 -83.
Third. Revised and
Enlarged Edition
E. V. Dehmlow / S. S. Dehmlow
Phase Transfer Catalysis
Phase Transfer Catalysis has matured
and so has this book. Certain PTCvariants have become standard
techniques in the lab, and PTC may be
on the brink of large-scale use.
This new edition describes important
new developments in PTC.
Furthermore, it has been extensively
updated and offers a comprehensive
list of very recent references.
To order please contact
your bookseller or:
VCH. P.O. Box 1011 61.
D-69451 Weinheim.
Fax (0) 62 01 - 60 61 84
VCH, Hardstrarse 10,
P.O. Box. CH-4020 Basel
New material has been added on
solid/liquid PTC
enantioselective reactions
metal-organic reactions
reduction and oxidation reactions
elimination and substitution
reactions.
1993. XIII, 499 pages with 49 tables.
Hardcover. DM 198,OO.
ISBN 3-527-28408-7
!002
f'l
YCH V~rlugs~eselDcl~u~I
mbH. D-69451 Weinheim, 1995
OS7ii-OX33~95~3418-2002
$ 10.0Of ,2510
AngeM,. Chem. Inr. Ed. Engl. 1995, 34. N o . I8
Документ
Категория
Без категории
Просмотров
1
Размер файла
375 Кб
Теги
treatment, gram, sepsis, endotoxin, possible, antagonisms, negativa, candidatus
1/--страниц
Пожаловаться на содержимое документа