High-Throughput Screen Reveals the Structure–Activity Relationship of the Antimicrobial Lasso Peptide Ubonodin,ACS Central Science

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High-Throughput Screen Reveals the Structure–Activity Relationship of the Antimicrobial Lasso Peptide Ubonodin
ACS Central Science ( IF 12.7 ) Pub Date : 2023-03-01 , DOI: 10.1021/acscentsci.2c01487
Alina Thokkadam ₁ , Truc Do ₁ , Xinchun Ran ₂ , Mark P Brynildsen _{1,

3} , Zhongyue J Yang _{2,

4,

5,

6} , A James Link _{1,

3,

7}

Affiliation

The Burkholderia cepacia complex (Bcc) is a group of bacteria including opportunistic human pathogens. Immunocompromised individuals and cystic fibrosis patients are especially vulnerable to serious infections by these bacteria, motivating the search for compounds with antimicrobial activity against the Bcc. Ubonodin is a lasso peptide with promising activity against Bcc species, working by inhibiting RNA polymerase in susceptible bacteria. We constructed a library of over 90 000 ubonodin variants with 2 amino acid substitutions and used a high-throughput screen and next-generation sequencing to examine the fitness of the entire library, generating the most comprehensive data set on lasso peptide activity so far. This screen revealed information regarding the structure–activity relationship of ubonodin over a large sequence space. Remarkably, the screen identified one variant with not only improved activity compared to wild-type ubonodin but also a submicromolar minimum inhibitory concentration (MIC) against a clinical isolate of the Bcc member Burkholderia cenocepacia. Ubonodin and several of the variants identified in this study had lower MICs against certain Bcc strains than those of many clinically approved antibiotics. Finally, the large library size enabled us to develop DeepLasso, a deep learning model that can predict the RNAP inhibitory activity of an ubonodin variant.

中文翻译：

高通量筛选揭示抗菌套索肽 Ubonodin 的结构-活性关系

洋葱伯克霍尔德菌复合体 (Bcc) 是一组细菌，包括机会性人类病原体。免疫功能低下的人和囊性纤维化患者特别容易受到这些细菌的严重感染，这促使人们寻找对 Bcc 具有抗菌活性的化合物。Ubonodin 是一种套索肽，对 Bcc 物种具有良好的活性，通过抑制易感细菌中的 RNA 聚合酶发挥作用。我们构建了一个包含超过 90,000 个具有 2 个氨基酸替换的 ubonodin 变体的库，并使用高通量筛选和下一代测序来检查整个库的适应性，生成了迄今为止关于套索肽活性的最全面的数据集。该筛选揭示了关于 ubonodin 在大序列空间中的结构-活性关系的信息。值得注意的是，新洋葱伯克霍尔德菌。Ubonodin 和本研究中发现的几种变体对某些 Bcc 菌株的 MIC 低于许多临床批准的抗生素。最后，大库大小使我们能够开发 DeepLasso，这是一种深度学习模型，可以预测 ubonodin 变体的 RNAP 抑制活性。

更新日期：2023-03-01

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