The bacterial cell wall is a quintessential drug target due to its critical role in colonization of the host, pathogen survival, and immune evasion. The dense cell wall glycocalyx contains distinctive monosaccharides that are absent from human cells, and proper assembly of monosaccharides into higher-order glycans is critical for bacterial fitness and pathogenesis. However, the systematic study and inhibition of bacterial glycosylation enzymes remains challenging. Bacteria produce glycans containing rare deoxy amino sugars refractory to traditional glycan analysis, complicating the study of bacterial glycans and the creation of glycosylation inhibitors. To ease the study of bacterial glycan function in the absence of detailed structural or enzyme information, we crafted metabolic inhibitors based on rare bacterial monosaccharide scaffolds. Metabolic inhibitors were assessed for their ability to interfere with glycan biosynthesis and fitness in pathogenic and symbiotic bacterial species. Three metabolic inhibitors led to dramatic structural and functional defects in Helicobacter pylori. Strikingly, these inhibitors acted in a bacteria-selective manner. These metabolic inhibitors will provide a platform for systematic study of bacterial glycosylation enzymes not currently possible with existing tools. Moreover, their selectivity will provide a pathway for the development of novel, narrow-spectrum antibiotics to treat infectious disease. Our inhibition approach is general and will expedite the identification of bacterial glycan biosynthesis inhibitors in a range of systems, expanding the glycochemistry toolkit.

中文翻译：

---

细菌聚糖生物合成的代谢抑制剂

细菌细胞壁是典型的药物靶标，因为它在宿主定植、病原体存活和免疫逃避中起着关键作用。致密的细胞壁糖萼含有人类细胞中不存在的独特单糖，将单糖正确组装成高级聚糖对于细菌适应性和发病机制至关重要。然而，细菌糖基化酶的系统研究和抑制仍然具有挑战性。细菌产生的聚糖含有稀有的脱氧氨基糖，传统的聚糖分析难以处理，这使得细菌聚糖的研究和糖基化抑制剂的产生变得复杂。为了在缺乏详细结构或酶信息的情况下简化细菌聚糖功能的研究，我们基于稀有细菌单糖支架制作了代谢抑制剂。评估了代谢抑制剂干扰致病菌和共生细菌物种的聚糖生物合成和适应性的能力。三种代谢抑制剂导致显着的结构和功能缺陷幽门螺杆菌。引人注目的是，这些抑制剂以细菌选择性方式起作用。这些代谢抑制剂将为细菌糖基化酶的系统研究提供一个平台，目前现有工具无法做到这一点。此外，它们的选择性将为开发治疗传染病的新型窄谱抗生素提供途径。我们的抑制方法是通用的，将加快在一系列系统中鉴定细菌聚糖生物合成抑制剂，扩展糖化学工具包。