Expanding the Bioactive Chemical Space of Anthrabenzoxocinones through Engineering the Highly Promiscuous Biosynthetic Modification Steps,ACS Chemical Biology

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Expanding the Bioactive Chemical Space of Anthrabenzoxocinones through Engineering the Highly Promiscuous Biosynthetic Modification Steps
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-12-19 00:00:00 , DOI: 10.1021/acschembio.7b00743
Xianyi Mei _{1,

2} , Xiaoli Yan ₂ , Hui Zhang ₂ , Mingjia Yu ₂ , Guangqing Shen ₂ , Linjun Zhou ₂ , Zixin Deng ₂ , Chun Lei ₃ , Xudong Qu _{1,

2}

Affiliation

Anthrabenzoxocinones (ABXs) including (−)-ABXs and (+)-ABXs are a group of bacterial FabF-specific inhibitors with potent antimicrobial activity of resistant strains. Optimization of their chemical structures is a promising method to develop potent antibiotics. Through biosynthetic investigation, we herein identified and characterized two highly promiscuous enzymes involved in the (−)-ABX structural modification. The promiscuous halogenase and methyltransferase can respectively introduce halogen-modifications into various positions of the ABX scaffolds and methylation to highly diverse substrates. Manipulation of their activity in both of the (−)-ABXs and (+)-ABXs biosyntheses led to the generation of 14 novel ABX analogues of both enantiomers. Bioactivity assessment revealed that a few of the analogues showed significantly improved antimicrobial activity, with the C3-hydroxyl and chlorine substitutions critical for their activity. This study enormously expands the bioactive chemical space of the ABX family and FabF-specific inhibitors. The disclosed broad-selective biosynthetic machineries and structure–activity relationship provide a solid basis for further generation of potent antimicrobial agents.

中文翻译：

通过设计高度混杂的生物合成修饰步骤来扩大蒽苯并噻吨酮的生物活性化学空间

包括（-）-ABXs和（+）-ABXs的蒽苯并氧杂蒽酮（ABXs）是一组细菌FabF特异性抑制剂，对耐药菌株具有强大的抗菌活性。优化其化学结构是开发有效抗生素的一种有前途的方法。通过生物合成研究，我们在此鉴定并鉴定了与（-）-ABX结构修饰有关的两种高度混杂的酶。混杂的卤化酶和甲基转移酶可分别将卤素修饰引入ABX支架的各个位置，并甲基化至高度多样化的底物。操纵其在（-）-ABX和（+）-ABXs生物合成中的活性导致了两种对映体的14种新颖ABX类似物的产生。生物活性评估表明，一些类似物显示出显着改善的抗菌活性，其中C3-羟基和氯取代对其活性至关重要。这项研究极大地扩展了ABX家族和FabF特异性抑制剂的生物活性化学空间。所公开的广泛选择的生物合成机制和结构-活性关系为进一步产生有效的抗菌剂提供了坚实的基础。

更新日期：2017-12-19

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