Preference of Bacterial Rhamnosyltransferases for 6-Deoxysugars Reveals a Strategy To Deplete O-Antigens.
Preference of Bacterial Rhamnosyltransferases for 6-Deoxysugars Reveals a Strategy To Deplete O-Antigens.
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DOI：
10.1021/jacs.3c03005
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发表时间：
2023-07-26
影响因子：
15
通讯作者：
Lupoli, Tania J.
中科院分区：
文献类型：
--
作者：
Harnagel, Alexa P.;Sheshova, Mia;Zheng, Meng;Zheng, Maggie;Skorupinska-Tudek, Karolina;Swiezewska, Ewa;Lupoli, Tania J.
细菌合成数百种细菌特异性或“稀有”糖，这些糖在哺乳动物细胞中不存在，并富含6-脱氧单糖，如l-鼠李糖（l-Rha）。在细菌中，l-Rha通过将核苷酸糖底物（供体）偶联至靶生物分子（受体）的鼠李糖基转移酶（RT）掺入聚糖中。由于l-Rha是参与存活或宿主感染的细菌聚糖的生物合成所必需的，因此RT代表了潜在的抗生素或抗病力靶标。然而，纯化的RT及其独特的细菌糖底物一直难以获得。在这里，我们使用合成的核苷酸稀有糖和糖脂类似物来检查底物识别由三个RT产生细胞被膜成分在不同的物种，包括一个已知的病原体。我们发现，细菌RT喜欢嘧啶核苷酸连接的6-脱氧糖，而不是那些含有C6-羟基，作为捐助者。虽然糖脂受体必须含有脂质，但类异戊二烯链长和立体化学可以变化。基于这些观察结果，我们表明，6-脱氧糖过渡态类似物抑制RT在体外，并降低革兰氏阴性细胞中的RT依赖性O-抗原多糖的水平。由于O-抗原是毒力因子，细菌特异性糖转移酶抑制代表了预防细菌感染的新策略。
Bacteria synthesize hundreds of bacteria-specific or “rare” sugars that are absent in mammalian cells and enriched in 6-deoxy monosaccharides such as l-rhamnose (l-Rha). Across bacteria, l-Rha is incorporated into glycans by rhamnosyltransferases (RTs) that couple nucleotide sugar substrates (donors) to target biomolecules (acceptors). Since l-Rha is required for the biosynthesis of bacterial glycans involved in survival or host infection, RTs represent potential antibiotic or antivirulence targets. However, purified RTs and their unique bacterial sugar substrates have been difficult to obtain. Here, we use synthetic nucleotide rare sugar and glycolipid analogs to examine substrate recognition by three RTs that produce cell envelope components in diverse species, including a known pathogen. We find that bacterial RTs prefer pyrimidine nucleotide-linked 6-deoxysugars, not those containing a C6-hydroxyl, as donors. While glycolipid acceptors must contain a lipid, isoprenoid chain length, and stereochemistry can vary. Based on these observations, we demonstrate that a 6-deoxysugar transition state analog inhibits an RT in vitro and reduces levels of RT-dependent O-antigen polysaccharides in Gram-negative cells. As O-antigens are virulence factors, bacteria-specific sugar transferase inhibition represents a novel strategy to prevent bacterial infections.
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DOI：
10.2174/1568005014606116
发表时间：
2001-08-01
期刊：
Current Drug Targets - Infectious Disorders
影响因子：
--
作者：
Ha, S.;Gross, B.;Walker, S.
通讯作者：
Walker, S.
影响因子：
3.2
作者：
He, Chao;Liu, Ning;Xiao, Yazhong
通讯作者：
Xiao, Yazhong
影响因子：
3.1
作者：
Dharuman, Suresh;Wang, Yichen;Crich, David
通讯作者：
Crich, David
影响因子：
14.9
作者：
Drula E;Garron ML;Dogan S;Lombard V;Henrissat B;Terrapon N
通讯作者：
Terrapon N
影响因子：
6.8
作者：
Giraud, MF;Naismith, JH
通讯作者：
Naismith, JH