Biosynthetic Interrogation of Soil Metagenomes Reveals Metamarin, an Uncommon Cyclomarin Congener with Activity against Mycobacterium tuberculosis,Journal of Natural Products

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Biosynthetic Interrogation of Soil Metagenomes Reveals Metamarin, an Uncommon Cyclomarin Congener with Activity against Mycobacterium tuberculosis
Journal of Natural Products ( IF 3.3 ) Pub Date : 2021-02-23 , DOI: 10.1021/acs.jnatprod.0c01104
Lei Li ₁ , Logan W MacIntyre ₁ , Thahmina Ali ₁ , Riccardo Russo ₂ , Bimal Koirala ₁ , Yozen Hernandez ₁ , Sean F Brady ₁

Affiliation

Tuberculosis (TB) remains one of the deadliest infectious diseases. Unfortunately, the development of antibiotic resistance threatens our current therapeutic arsenal, which has necessitated the discovery and development of novel antibiotics against drug-resistant Mycobacterium tuberculosis (Mtb). Cyclomarin A and rufomycin I are structurally related cyclic heptapeptides assembled by nonribosomal peptide synthetases (NRPSs), which show potent anti-Mtb activity with a new cellular target, the caseinolytic protein ClpC1. An NRPS adenylation domain survey using DNA extracted from ∼2000 ecologically diverse soils found low cyclomarin/rufomycin biosynthetic diversity. In this survey, a family of cyclomarin/rufomycin-like biosynthetic gene clusters (BGC) that encode metamarin, an uncommon cyclomarin congener with potent activity against both Mtb H37Rv and multidrug-resistant Mtb clinical isolates was identified. Metamarin effectively inhibits Mtb growth in murine macrophages and increases the activities of ClpC1 ATPase and the associated ClpC1/P1/P2 protease complex, thus causing cell death by uncontrolled protein degradation.

中文翻译：

土壤宏基因组的生物合成研究揭示了 Metamarin，一种罕见的 Cyclomarin 同源物，具有抗结核分枝杆菌的活性

结核病 (TB) 仍然是最致命的传染病之一。不幸的是，抗生素耐药性的发展威胁着我们目前的治疗武器库，这需要发现和开发针对耐药结核分枝杆菌( Mtb )的新型抗生素。Cyclomarin A 和 rufomycin I 是结构相关的环状七肽，由非核糖体肽合成酶 (NRPS) 组装，显示出有效的抗Mtb活性与新的细胞靶标，酪蛋白分解蛋白 ClpC1。使用从~2000 个生态多样的土壤中提取的 DNA 进行的 NRPS 腺苷酸化域调查发现环马素/芸香霉素生物合成多样性较低。在这项调查中，鉴定了一个编码 metamarin 的 cyclomarin/rufomycin 样生物合成基因簇 (BGC) 家族，这是一种不常见的 cyclomarin 同源物，对Mtb H37Rv 和多药耐药Mtb临床分离株都具有强效活性。Metamarin 有效抑制鼠巨噬细胞中Mtb 的生长，并增加 ClpC1 ATPase 和相关的 ClpC1/P1/P2 蛋白酶复合物的活性，从而通过不受控制的蛋白质降解导致细胞死亡。

更新日期：2021-04-23

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