Sharon Nathan
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Biochim Biophys Acta. 2006 Apr;1760(4):527-37. doi: 10.1016/j.bbagen.2005.12.008. Epub 2006 Jan 18.
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 1 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 1 fimbriated E. coli, being up to 1000 times more active than MealphaMan, 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 up 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.
致病生物体与宿主组织的黏附是大多数传染病发生的前提条件。在许多系统中，这种黏附是由存在于感染性生物体表面的凝集素介导的，这些凝集素与宿主组织表面的互补碳水化合物结合。凝集素缺陷型突变体通常缺乏引发感染的能力。细菌凝集素通常呈细长的亚微观多亚基蛋白质附属物形式，称为菌毛（或伞毛）。其中研究最充分的是大肠杆菌的甘露糖特异性1型菌毛、半乳糖特异性P菌毛和N-乙酰葡糖胺特异性菌毛。细菌表面凝集素识别的可溶性碳水化合物可在体外阻断细菌与动物细胞的黏附。芳香族α-甘露糖苷是1型菌毛化大肠杆菌的有效抑制剂，其活性比甲基α-甘露糖苷高1000倍，亲和力在纳摩尔范围内。这是由于菌毛单糖结合位点旁边存在一个疏水区域，最近的X射线研究证明了这一点。多价糖类（如糖蛋白或树枝状大分子）也是体外细菌黏附的强力抑制剂。非常重要的是，已证明凝集素抑制性糖类可保护小鼠、兔子、小牛和猴子免受携带凝集素细菌的实验性感染。由于抗黏附剂不是通过杀死病原体或阻止其生长来发挥作用的，因此对这类药剂产生抗性的菌株出现的速率很可能明显低于对抗生素产生抗性的菌株。合适的糖类还可抑制碳水化合物特异性毒素与细胞的结合，其中包括痢疾志贺氏菌1型毒素以及大肠杆菌同源维罗毒素，它们对半乳糖具有特异性。经过适当设计的多价配体在体外对毒素结合的抑制作用比单价配体强六个数量级，并且它们可保护小鼠免受志贺氏菌毒素的侵害。上述数据为传染病抗黏附治疗的可行性提供了明确证据，尽管这种治疗方法在人类中尚未取得成功。然而，总而言之，毫无疑问，微生物凝集素抑制剂在不久的将来将加入传染病治疗药物的行列。
