Inhibition of the GDP-d-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes,ACS Chemical Biology

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Inhibition of the GDP-d-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-11-25 , DOI: 10.1021/acschembio.0c00426
Laura Beswick ₁ , Eleni Dimitriou ₁ , Sanaz Ahmadipour ₂ , Ayesha Zafar ₃ , Martin Rejzek ₄ , Jóhannes Reynisson ₅ , Robert A Field ₂ , Gavin J Miller ₁

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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.

中文翻译：

使用靶向糖核苷酸探针抑制铜绿假单胞菌的 GDP-d-甘露糖脱氢酶

囊性纤维化患者患慢性肺部感染的风险极高。在其一生中，一种细菌菌株，特别是铜绿假单胞菌，成为主要病原体。细菌菌株的 mucA 基因发生功能丧失突变，导致粘液转化，从而导致海藻酸胞外多糖的大量分泌。因此，阻止粘液型铜绿假单胞菌感染中藻酸盐产生的策略至关重要。为了帮助实现这一目标，我们开发了一系列糖核苷酸工具来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 催化海藻酸盐结构单元二磷酸鸟苷甘露糖醛酸的不可逆形成。使用化学酶策略，我们获得了一系列修饰的糖核苷酸，鉴定出鸟苷二磷酸甘露糖的 C6-酰胺衍生物作为 GMD 的微摩尔抑制剂。这一发现为开发更广泛的 GMD 抑制策略提供了框架。

更新日期：2020-12-18

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