Metagenome-Guided Analogue Synthesis Yields Improved Gram-Negative-Active Albicidin- and Cystobactamid-Type Antibiotics,Angewandte Chemie International Edition

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Metagenome-Guided Analogue Synthesis Yields Improved Gram-Negative-Active Albicidin- and Cystobactamid-Type Antibiotics
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2021-08-05 , DOI: 10.1002/anie.202104874
zongqiang wang ₁ , Amanda Kasper ₂ , Rabia Mehmood ₂ , Melinda Ternei ₂ , Shaogang Li ₃ , Joel S Freundlich ₄ , Sean Brady ₅

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Natural products are a major source of new antibiotics. Here we utilize biosynthetic instructions contained within metagenome-derived congener biosynthetic gene clusters (BGCs) to guide the synthesis of improved antibiotic analogues. Albicidin and cystobactamid are the first members of a new class of broad-spectrum ρ-aminobenzoic acid (PABA)-based antibiotics. Our search for PABA-specific adenylation domain sequences in soil metagenomes revealed that BGCs in this family are common in nature. Twelve BGCs that were bio-informatically predicted to encode six new congeners were recovered from soil metagenomic libraries. Synthesis of these six predicted structures led to the identification of potent antibiotics with changes in their spectrum of activity and the ability to circumvent resistance conferred by endopeptidase cleavage enzymes.

中文翻译：

宏基因组引导的类似物合成产生改良的革兰氏阴性活性 Albicidin 和 Cystobactamid 型抗生素

天然产物是新抗生素的主要来源。在这里，我们利用宏基因组衍生的同源生物合成基因簇 (BGC) 中包含的生物合成指令来指导改进的抗生素类似物的合成。Albicidin 和cystobactamid 是一类新的广谱对氨基苯甲酸 (PABA) 抗生素的首批成员。我们在土壤宏基因组中寻找 PABA 特异性腺苷酸化域序列表明，该家族中的 BGC 在自然界中很常见。从土壤宏基因组文库中回收了 12 个被生物信息学预测编码 6 个新同源物的 BGC。这六种预测结构的合成导致了有效抗生素的鉴定，它们的活性谱发生了变化，并且能够规避内肽酶切割酶赋予的抗性。

更新日期：2021-09-27

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