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邻氨基苯甲酸对细菌细胞壁生物合成必需酶——十一异戊烯基焦磷酸合酶（UppS）的抑制剂作用

Anthranilic Acid Inhibitors of Undecaprenyl Pyrophosphate Synthase (UppS), an Essential Enzyme for Bacterial Cell Wall Biosynthesis.

作者信息

Jukič Marko, Rožman Kaja, Sova Matej, Barreteau Hélène, Gobec Stanislav

机构信息

Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.

Bacterial Cell Envelopes and Antibiotics Group, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.

出版信息

Front Microbiol. 2019 Jan 14;9:3322. doi: 10.3389/fmicb.2018.03322. eCollection 2018.

DOI:10.3389/fmicb.2018.03322
PMID:30692977
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6339874/
Abstract

We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from UppS is an essential enzyme in the biosynthesis of bacterial cell wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new -double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antibacterial drug design. A pharmacophore model was designed on a known bisphosphonate and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three anthranilic acid derivatives with promising inhibitory activity against UppS. Compound displayed high inhibitory potency (IC = 25 μM) and good antibacterial activity against BW25113 Δ strain (MIC = 0.5 μg/mL).

摘要

我们报告了虚拟筛选在发现来自[具体来源未提及]的十一异戊烯基焦磷酸合酶（UppS）新抑制剂中的成功应用。UppS是细菌细胞壁生物合成中的一种关键酶。它催化法呢基焦磷酸（FPP）与八个连续的异戊烯基焦磷酸单元（IPP）缩合，在此过程中形成新的双键，以生成十一异戊烯基焦磷酸。后者作为肽聚糖合成的脂质载体，因此是抗菌药物设计中的一个重要靶点。基于一种已知的双膦酸盐设计了一个药效团模型，并用于制备一个富集的化合物库，该库进一步对接至通过分子动力学实验生成的UppS构象集合中。对接得到了三种对UppS具有有前景抑制活性的邻氨基苯甲酸衍生物。化合物[具体化合物未提及]表现出高抑制效力（IC = 25 μM），并且对BW25113 Δ菌株具有良好的抗菌活性（MIC = 0.5 μg/mL）。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/62f135a4d02b/fmicb-09-03322-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/ae26ec28f306/fmicb-09-03322-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/c25a426aedfd/fmicb-09-03322-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/50df9b0345fc/fmicb-09-03322-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/cd1e9a98c12e/fmicb-09-03322-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/c799857bc680/fmicb-09-03322-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/15d4006f1b3b/fmicb-09-03322-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/83dd902699ed/fmicb-09-03322-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/62f135a4d02b/fmicb-09-03322-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/ae26ec28f306/fmicb-09-03322-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/c25a426aedfd/fmicb-09-03322-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/50df9b0345fc/fmicb-09-03322-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/cd1e9a98c12e/fmicb-09-03322-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/c799857bc680/fmicb-09-03322-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/15d4006f1b3b/fmicb-09-03322-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/83dd902699ed/fmicb-09-03322-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ed6/6339874/62f135a4d02b/fmicb-09-03322-g008.jpg

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