Inhibition of the GDP-D-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes
Inhibition of the GDP-D-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes
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DOI：
10.1021/acschembio.0c00426
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发表时间：
2020-12-18
影响因子：
4
通讯作者：
Miller, Gavin J.
中科院分区：
文献类型：
--
作者：
Beswick, Laura;Dimitriou, Eleni;Miller, Gavin J.
囊性纤维化患者感染慢性肺部感染的风险极高。在他们的一生中，一种特别的细菌菌株，铜绿假单胞菌，成为主要的病原体。细菌菌株导致粘液A基因功能丧失突变，导致粘液转化，导致胞外多糖海藻酸盐的大量分泌。因此，在粘液性铜绿假单胞菌感染中停止产生藻酸盐的策略至关重要。为了帮助这一点，一系列的糖核苷酸工具已经被开发出来，以探测对藻酸盐生物合成至关重要的酶-鸟苷二磷酸甘露糖脱氢酶(GMD)。GMD催化不可逆的海藻酸组分--鸟苷二磷酸甘露醛的形成。使用化学酶策略，我们获得了一系列修饰的糖核苷酸，鉴定了鸟苷二磷酸甘露糖的C6-酰胺衍生物是GMD的微摩尔抑制物。这一发现为开发更广泛的针对GMD的抑制策略提供了一个框架。
Sufferers of cystic fibrosis are at extremely high risk for contracting chronic lung infections. Over their lifetime, one bacterial strain in particular, Pseudomonas aeruginosa, becomes the dominant pathogen. Bacterial strains incur loss-of-function mutations in the mucA gene that lead to a mucoid conversion, resulting in copious secretion of the exopolysaccharide alginate. Strategies that stop the production of alginate in mucoid Pseudomonas aeruginosa infections are therefore of paramount importance. To aid in this, a series of sugar nucleotide tools to probe an enzyme critical to alginate biosynthesis, guanosine diphosphate mannose dehydrogenase (GMD), have been developed. GMD catalyzes the irreversible formation of the alginate building block, guanosine diphosphate mannuronic acid. Using a chemoenzymatic strategy, we accessed a series of modified sugar nucleotides, identifying a C6-amide derivative of guanosine diphosphate mannose as a micromolar inhibitor of GMD. This discovery provides a framework for wider inhibition strategies against GMD to be developed.