Studies on the Biological Mechanisms of Antibiotics

 描述(申请人提供)：抗药性细菌感染对人类健康构成严重威胁。耐药性正在增加，而对新抗生素和可能的新靶点的研究却滞后。革兰氏阳性和革兰氏阴性细菌都被一种交联型碳水化合物聚合物--肽聚糖(PG)包围。这种聚合物对细菌的生存至关重要，因为它可以稳定细胞膜，使其免受高内渗透压的影响。肽聚糖的生物合成是抗生素的主要目标，因为干扰这一过程会导致细胞裂解。事实上，β-内酰胺类和糖肽类抗生素会抑制PG的生物合成。许多PG生物合成酶已经成为临床上使用的抗生素的靶标；然而，有一类特别有希望的靶标--肽聚糖糖基转移酶(PGTS)仍然没有被开发出来。本研究计划的重点是寻找PGTS的抑制剂。这些酶是有吸引力的靶标，因为它们的功能是必不可少的，它们的结构在所有细菌中都高度保守，它们没有哺乳动物的同系物，而且它们位于质膜的外表面，这使得它们比细胞内的酶更容易被抑制剂所利用。这里描述的研究构成了一个综合的、全面的计划，利用文库筛选、合成有机化学、生化和细胞分析、结构研究和细菌遗传学来发现和开发PGT抑制剂。这项拟议的工作可能会带来治疗抗生素耐药性感染的新化合物。

 DESCRIPTION (provided by applicant): Antibiotic resistant bacterial infections pose a serious threat to human health. Resistance is increasing while research into new antibiotics and possible new targets is lagging. Both Gram-positive and Gram-negative bacteria are surrounded by a cross-linked carbohydrate polymer, peptidoglycan (PG). This polymer is essential for bacterial survival because it stabilizes the cell membrane against high internal osmotic pressures. Peptidoglycan biosynthesis is a major target for antibiotics because interfering with this process leads to cell lysis. Indeed, the beta-lactams and glycopeptide antibiotics inhibit PG biosynthesis. Many PG biosynthetic enzymes are already targeted by clinically used antibiotics; however, one class of especially promising targets, the peptidoglycan glycosyltransferases (PGTs), remains unexploited. This research program is focused on discovering inhibitors of PGTs. These enzymes are attractive targets because their functions are essential, their structures are highly conserved in all bacteria, they have no mammalian homologs and they are located on the outer surface of the plasma membrane, which makes them more accessible to inhibitors than intracellular enzymes. The research described here constitutes an integrated, comprehensive program to discover and develop PGT inhibitors using library screening, synthetic organic chemistry, biochemical and cellular assays, structural studies, and bacterial genetics. The proposed work may lead to new compounds to treat antibiotic-resistant infections.