Inhibition of Nonessential Bacterial Targets: Discovery of a Novel Serine O-Acetyltransferase Inhibitor.,ACS Medicinal Chemistry Letters

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Inhibition of Nonessential Bacterial Targets: Discovery of a Novel Serine O-Acetyltransferase Inhibitor.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-02-13 , DOI: 10.1021/acsmedchemlett.9b00627
Joana Magalhães ₁ , Nina Franko ₁ , Samanta Raboni _{1,

2} , Giannamaria Annunziato ₁ , Päivi Tammela ₃ , Agostino Bruno ₁ , Stefano Bettati _{2,

4,

5} , Andrea Mozzarelli _{1,

2,

5} , Marco Pieroni _{1,

6} , Barbara Campanini ₁ , Gabriele Costantino _{1,

6,

7}

Affiliation

In ϒ-proteobacteria and Actinomycetales, cysteine biosynthetic enzymes are indispensable during persistence and become dispensable during growth or acute infection. The biosynthetic machinery required to convert inorganic sulfur into cysteine is absent in mammals; therefore, it is a suitable drug target. We searched for inhibitors of Salmonella serine acetyltransferase (SAT), the enzyme that catalyzes the rate-limiting step of l-cysteine biosynthesis. The virtual screening of three ChemDiv focused libraries containing 91 243 compounds was performed to identify potential SAT inhibitors. Scaffold similarity and the analysis of the overall physicochemical properties allowed the selection of 73 compounds that were purchased and evaluated on the recombinant enzyme. Six compounds displaying an IC50 <100 μM were identified via an indirect assay using Ellman's reagent and then tested on a Gram-negative model organism, with one of them being able to interfere with bacterial growth via SAT inhibition.

中文翻译：

抑制不必要的细菌靶标：一种新型丝氨酸O-乙酰基转移酶抑制剂的发现。

在β-变形杆菌和放线菌中，半胱氨酸生物合成酶在持久性过程中是必不可少的，而在生长或急性感染时则是必不可少的。在哺乳动物中不存在将无机硫转化为半胱氨酸所需的生物合成机制。因此，它是合适的药物靶标。我们寻找沙门氏菌丝氨酸乙酰转移酶（SAT）的抑制剂，该酶催化L-半胱氨酸生物合成的限速步骤。对三个包含91 243种化合物的ChemDiv聚焦库进行了虚拟筛选，以鉴定潜在的SAT抑制剂。支架相似性和整体理化性质分析允许选择购买的73种化合物，并在重组酶上进行评估。六种化合物的IC50 <

更新日期：2020-02-13

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