Carbohydrates as future anti-adhesion drugs for infectious diseases

被引:398
作者
Sharon, N [1 ]
机构
[1] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel
来源
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS | 2006年 / 1760卷 / 04期
关键词
Escherichia coli; fimbriae (pili); bacterial lectin; combining site; three-dimensional strcuture;
D O I
10.1016/j.bbagen.2005.12.008
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Adhesion of pathogenic organisms to host tissues is the prerequisite for the initiation of the majority of infectious diseases. In many systems, it is mediated by lectins present on the Surface of the infectious organism that bind to complementary carbohydrates on the surface of the host tissues. Lectin-deficient mutants often lack the ability to initiate infection. The bacterial lectins are typically in the form of elongated submicroscopic multi-subunit protein appendages, known as fimbriae (or pili). The best characterized of these are the mannose-specific type I fimbriae, the galabiose-specific P fimbriae and the N-acetylglucosamine-specific fimbriae of Escherichia coli. Soluble carbohydrates recognized by the bacterial surface lectins block the adhesion of the bacteria to animal cells in vitro. Aromatic alpha-mannosides are potent inhibitors of type I fimbriated E. coli, being Lip to 1000 times more active than Me alpha Man, with affinities in the nanomolar range. This is due to the presence of a hydrophobic region next to the monosaccharide-binding site of the fimbriae, as recently demonstrated by X-ray studies. Polyvalent saccharides (e.g., neoglycoproteins or dendrimers) are also powerful inhibitors of bacterial adhesion in vitro. Very significantly, lectin-inhibitory saccharides have been shown to protect mice, rabbits, calves and monkeys against experimental infection by lectin-carrying bacteria. Since anti-adhesive agents do not act by killing or arresting the growth of the pathogens, it is very likely that strains resistant to such agents will emerge at a markedly lower rate than of strains that are resistant to antibiotics. Suitable sugars also inhibit the binding to cells of carbohydrate-specific toxins, among them those of Shigella dysenteriae Type 1, and of the homologous Verotoxins of E. coli, specific for galabiose. Appropriately designed polyvalent ligands are Lip to six orders of magnitude stronger inhibitors of toxin binding in vitro than the monovalent ones, and they protect mice against the Shigella toxin. The above data provide clear proof for the feasibility of anti-adhesion therapy of infectious diseases, although this has not yet been successful in humans. All in all, however, there is little doubt that inhibitors of microbial lectins will in the near future join the arsenal of drugs for therapy of infectious diseases. (c) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:527 / 537
页数:11
相关论文
共 83 条
[1]   PROTECTION AGAINST ESCHERICHIA-COLI-INDUCED URINARY-TRACT INFECTIONS WITH HYBRIDOMA ANTIBODIES DIRECTED AGAINST TYPE-1 FIMBRIAE OR COMPLEMENTARY D-MANNOSE RECEPTORS [J].
ABRAHAM, SN ;
BABU, JP ;
GIAMPAPA, CS ;
HASTY, DL ;
SIMPSON, WA ;
BEACHEY, EH .
INFECTION AND IMMUNITY, 1985, 48 (03) :625-628
[2]   Fimbriae-mediated host-pathogen cross-talk [J].
Abraham, SN ;
Jonsson, AB ;
Normark, S .
CURRENT OPINION IN MICROBIOLOGY, 1998, 1 (01) :75-81
[3]   ANTI-ADHESIVE PROPERTIES OF A QUATERNARY STRUCTURE-SPECIFIC HYBRIDOMA ANTIBODY AGAINST TYPE-1 FIMBRIAE OF ESCHERICHIA-COLI [J].
ABRAHAM, SN ;
HASTY, DL ;
SIMPSON, WA ;
BEACHEY, EH .
JOURNAL OF EXPERIMENTAL MEDICINE, 1983, 158 (04) :1114-1128
[4]   PREVENTION OF COLONIZATION OF THE URINARY-TRACT OF MICE WITH ESCHERICHIA-COLI BY BLOCKING OF BACTERIAL ADHERENCE WITH METHYL ALPHA-D-MANNOPYRANOSIDE [J].
ARONSON, M ;
MEDALIA, O ;
SCHORI, L ;
MIRELMAN, D ;
SHARON, N ;
OFEK, I .
JOURNAL OF INFECTIOUS DISEASES, 1979, 139 (03) :329-332
[5]   Adherence of Streptococcus pneumoniae to respiratory epithelial cells is inhibited by sialylated oligosaccharides [J].
Barthelson, R ;
Mobasseri, A ;
Zopf, D ;
Simon, P .
INFECTION AND IMMUNITY, 1998, 66 (04) :1439-1444
[6]   Tamm-Horsfall protein knockout mice are more prone to urinary tract infection [J].
Bates, JM ;
Raffi, HM ;
Prasadan, K ;
Mascarenhas, R ;
Laszik, Z ;
Maeda, N ;
Hultgren, SJ ;
Kumar, S .
KIDNEY INTERNATIONAL, 2004, 65 (03) :791-797
[7]   Escherichia coli, fimbriae, bacterial persistence and host response induction in the human urinary tract [J].
Bergsten, G ;
Wullt, B ;
Svanborg, C .
INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY, 2005, 295 (6-7) :487-502
[8]   LECTINOPHAGOCYTOSIS OF TYPE-1 FIMBRIATED (MANNOSE-SPECIFIC) ESCHERICHIA-COLI IN THE MOUSE PERITONEUM [J].
BERNHARD, W ;
GBARAH, A ;
SHARON, N .
JOURNAL OF LEUKOCYTE BIOLOGY, 1992, 52 (03) :343-348
[9]   Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin [J].
Bouckaert, J ;
Berglund, J ;
Schembri, M ;
De Genst, E ;
Cools, L ;
Wuhrer, M ;
Hung, CS ;
Pinkner, J ;
Slättegård, R ;
Zavialov, A ;
Choudhury, D ;
Langermann, S ;
Hultgren, SJ ;
Wyns, L ;
Klemm, P ;
Oscarson, S ;
Knight, SD ;
De Greve, H .
MOLECULAR MICROBIOLOGY, 2005, 55 (02) :441-455
[10]   The fimbrial adhesin F17-G of enterotoxigenic Escherichia coli has an immunoglobulin-like lectin domain that binds N-acetylglucosamine [J].
Buts, L ;
Bouckaert, J ;
De Genst, E ;
Loris, R ;
Oscarson, S ;
Lahmann, M ;
Messens, J ;
Brosens, E ;
Wyns, L ;
De Greve, H .
MOLECULAR MICROBIOLOGY, 2003, 49 (03) :705-715