Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA.
Department of Molecular Biology, Princeton University, USA.
Angew Chem Int Ed Engl. 2019 Apr 23;58(18):5973-5977. doi: 10.1002/anie.201901342. Epub 2019 Mar 28.
The majority of natural product biosynthetic gene clusters in bacteria are silent under standard laboratory growth conditions, making it challenging to uncover any antibiotics that they may encode. Herein, bioactivity assays are combined with high-throughput elicitor screening (HiTES) to access cryptic, bioactive metabolites. Application of this strategy in Saccharopolyspora cebuensis, with inhibition of Escherichia coli growth as a read-out, led to the identification of a novel lanthipeptide, cebulantin. Extensive NMR spectroscopic analysis allowed the elucidation of the structure of cebulantin. Subsequent bioactivity assays revealed it to be an antibiotic selective for Gram-negative bacteria, especially against Vibrio species. This approach, referred to as bioactivity-HiTES, has the potential to uncover cryptic metabolites with desired biological activities that are hidden in microbial genomes.
大多数细菌中的天然产物生物合成基因簇在标准实验室生长条件下处于沉默状态，这使得发现它们可能编码的抗生素变得具有挑战性。在此，生物活性测定与高通量诱导剂筛选（HiTES）相结合，以获得隐藏的生物活性代谢产物。该策略在嗜糖多孢菌中的应用，以抑制大肠杆菌生长作为读出，导致了一种新型的硫肽类抗生素，cebulantin 的鉴定。广泛的 NMR 光谱分析允许阐明 cebulantin 的结构。随后的生物活性测定表明，它是一种对革兰氏阴性菌，特别是对弧菌属具有选择性的抗生素。这种方法称为生物活性-HiTES，具有发现隐藏在微生物基因组中的具有所需生物活性的隐藏代谢产物的潜力。
