Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, UK.
Carbohydr Res. 2013 Oct 18;380:70-5. doi: 10.1016/j.carres.2013.07.006. Epub 2013 Jul 20.
The increasing prevalence of multi-drug resistant bacteria is driving efforts in the development of new antibacterial agents. This includes a resurgence of interest in the Gram-negative bacteria lipopolysaccharide (LPS) biosynthesis enzymes as drug targets. The six carbon acidic sugar 2-keto-3-deoxymanno-octulosonic acid (Kdo) is a component of the lipid A moiety of the LPS in Gram-negative bacteria. In most cases the lipid A substituted by Kdo is the minimum requirement for cell growth, thus presenting the possibility of targeting either the synthesis or incorporation of Kdo for the development of antibacterial agents. Indeed, potent in vitro inhibitors of Kdo biosynthesis enzymes have been reported but have so far failed to show sufficient in vivo action against Gram-negative bacteria. As part of an effort to design more potent antibacterial agents targeting Kdo biosynthesis, the crystal structures of the key Kdo biosynthesis enzymes from Escherichia coli have been solved and their structure based mechanisms characterized. In eukaryotes, Kdo is found as a component of the pectic polysaccharide rhamnogalacturonan II in the plant primary cell wall. Interestingly, despite incorporating Kdo into very different macromolecules the Kdo biosynthesis and activation pathway is almost completely conserved between plants and bacteria. This raises the possibility for plant research to exploit the increasingly detailed knowledge and resources being generated by the microbiology community. Likewise, insights into Kdo biosynthesis in plants will be potentially useful in efforts to produce new antimicrobial compounds.
越来越多的多药耐药菌的出现推动了新抗菌药物的研发。这包括人们对革兰氏阴性菌脂多糖（LPS）生物合成酶作为药物靶点的重新关注。六碳酸性糖 2-酮-3-脱氧甘露壬糖酸（Kdo）是革兰氏阴性菌 LPS 脂质 A 部分的一个组成部分。在大多数情况下，被 Kdo 取代的脂质 A 是细胞生长的最低要求，因此有可能针对 Kdo 的合成或掺入来开发抗菌药物。事实上，已经报道了 Kdo 生物合成酶的有效体外抑制剂，但迄今为止，它们对革兰氏阴性菌的体内作用还不够。作为设计针对 Kdo 生物合成的更有效抗菌药物的一部分，已经解决了来自大肠杆菌的关键 Kdo 生物合成酶的晶体结构，并对其基于结构的机制进行了表征。在真核生物中，Kdo 是植物初生细胞壁中果胶多糖鼠李半乳糖醛酸聚糖 II 的一个组成部分。有趣的是，尽管将 Kdo 掺入到非常不同的大分子中，但 Kdo 的生物合成和激活途径在植物和细菌之间几乎完全保守。这为植物研究提供了利用微生物学领域日益详细的知识和资源的可能性。同样，对植物中 Kdo 生物合成的深入了解也可能有助于开发新的抗菌化合物。
