Synthesis of Lipid‐Carbohydrate‐Peptidyl‐RNA Conjugates to Explore the Limits Imposed by the Substrate Specificity of Cell Wall Enzymes on the Acquisition of Drug Resistance,Chemistry - A European Journal

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Synthesis of Lipid‐Carbohydrate‐Peptidyl‐RNA Conjugates to Explore the Limits Imposed by the Substrate Specificity of Cell Wall Enzymes on the Acquisition of Drug Resistance
Chemistry - A European Journal ( IF 3.9 ) Pub Date : 2018-09-06 , DOI: 10.1002/chem.201802360
Matthieu Fonvielle ₁ , Ahmed Bouhss _{2,

3} , Coralie Hoareau ₁ , Delphine Patin ₂ , Dominique Mengin-Lecreulx ₂ , Laura Iannazzo _{4,

5} , Nicolas Sakkas _{4,

5} , Affaf El Sagheer _{6,

7} , Tom Brown ₇ , Mélanie Ethève-Quelquejeu _{4,

5} , Michel Arthur ₁

Affiliation

Conjugation of RNA with multiple partners to obtain mimics of complex biomolecules is limited by the identification of orthogonal reactions. Here, lipid‐carbohydrate‐peptidyl‐RNA conjugates were obtained by post‐functionalization reactions, solid‐phase synthesis, and enzymatic steps, to generate molecules mimicking the substrates of FmhB, an essential peptidoglycan synthesis enzyme of Staphylococcus aureus. Mimics of Gly‐tRNA^Gly and lipid intermediate II (undecaprenyl‐diphospho‐disaccharide‐pentapeptide) were combined in a single “bi‐substrate” inhibitor (IC₅₀=56 nm). The synthetic route was exploited to generate substrates and inhibitors containing d‐lactate residue (d‐Lac) instead of d‐Ala at the C‐terminus of the pentapeptide stem, a modification responsible for vancomycin resistance in the enterococci. The substitution impaired recognition of peptidoglycan precursors by FmhB. The associated fitness cost may account for limited dissemination of vancomycin resistance genes in S. aureus.

中文翻译：

脂质碳水化合物肽基RNA的合成共轭，以探索细胞壁酶的底物特异性对获得耐药性的限制

鉴定正交反应限制了RNA与多个配偶体的缀合以获得复杂生物分子的模拟物。在这里，通过功能化后反应，固相合成和酶促步骤获得了脂质碳水化合物肽基RNA缀合物，以生成模拟金黄色葡萄球菌必不可少的肽聚糖合成酶FmhB底物的分子。甘氨酸酰-tRNA的模拟物^甘氨酸和脂质中间体II（十一异戊烯二磷酸二糖五肽）合并在一个单一的“双向基板”抑制剂（IC ₅₀ = 56Ñ米）。利用合成途径生成了含有d-乳酸残基的底物和抑制剂（d-Lac）代替五肽茎C-末端的d - Ala ，这是引起肠球菌对万古霉素耐药的修饰。取代削弱了FmhB对肽聚糖前体的识别。相关的适应性花费可能解释了在金黄色葡萄球菌中万古霉素抗性基因的有限传播。

更新日期：2018-09-06

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