Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Rutgers, The State University of New Jersey, International Center for Public Health, 225 Warren Street, Newark, New Jersey 07103, United States.
J Nat Prod. 2021 Apr 23;84(4):1056-1066. doi: 10.1021/acs.jnatprod.0c01104. Epub 2021 Feb 23.
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 (). Cyclomarin A and rufomycin I are structurally related cyclic heptapeptides assembled by nonribosomal peptide synthetases (NRPSs), which show potent anti- 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 H37Rv and multidrug-resistant clinical isolates was identified. Metamarin effectively inhibits 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.
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，这就需要发现和开发针对耐药性的新型抗生素。环马菌素 A 和鲁福霉素 I 是由非核糖体肽合成酶（NRPS）组装的结构相关的环状七肽，它们对新的细胞靶标——组织蛋白酶 ClpC1 表现出强大的抗菌活性。使用从约 2000 种生态多样的土壤中提取的 DNA 对 NRPS 腺苷酸化结构域进行调查，发现环马菌素/鲁福霉素生物合成的多样性较低。在这项调查中，发现了一组环马菌素/鲁福霉素样生物合成基因簇（BGC），它们编码代谢马霉素，这是一种不常见的环马菌素同系物，对 H37Rv 和多药耐药的临床分离株均具有强大的活性。代谢马霉素能有效抑制鼠巨噬细胞中的生长，并增加 ClpC1 ATP 酶和相关的 ClpC1/P1/P2 蛋白酶复合物的活性，从而导致失控的蛋白降解引起细胞死亡。
