TY - JOUR

T1 - Comparative Genomic and Metabolic Analysis of Streptomyces sp. RB110 Morphotypes Illuminates Genomic Rearrangements and Formation of a New 46-Membered Antimicrobial Macrolide

AU - Um, Soohyun

AU - Guo, Huijuan

AU - Thiengmag, Sirinthra

AU - Benndorf, René

AU - Murphy, Robert

AU - Rischer, Maja

AU - Braga, Daniel

AU - Poulsen, Michael

AU - de Beer, Z. Wilhelm

AU - Lackner, Gerald

AU - Beemelmanns, Christine

N1 - Funding Information: This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - CRC 1127/2 ChemBioSys—project ID 239748522 and BE 4799/3-1 to C.B. S.U. thanks the Humboldt Foundation for a postdoctoral fellowship, and S.T., D.B., and G.L. thank the Carl Zeiss Foundation for funding. R.M. and M.P. are supported by a European Research Council Consolidator Grant (771349). We wish to thank H. Heinecke (Hans Knöll Institute, Jena) for measurement of NMR spectra and C. Weigel (Hans Knöll Institute, Jena) and H.-M. Dahse (Hans Knöll Institute, Jena) for preliminary bioactivity studies. Publisher Copyright: ©

PY - 2021

Y1 - 2021

N2 - Morphotype switches frequently occur in Actinobacteria and are often associated with disparate natural product production. Here, we report on differences in the secondary metabolomes of two morphotypes of a Streptomyces species, including the discovery of a novel antimicrobial glycosylated macrolide, which we named termidomycin A. While exhibiting an unusual 46-member polyene backbone, termidomycin A (1) shares structural features with the clinically important antifungal agents amphotericin B and nystatin A1. Genomic analyses revealed a biosynthetic gene cluster encoding for a putative giant type I polyketide synthase (PKS), whose domain structure allowed us to propose the relative configuration of the 46-member macrolide. The architecture of the biosynthetic gene cluster was different in both morphotypes, thus leading to diversification of the product spectrum. Given the high frequency of genomic rearrangements in Streptomycetes, the metabolic analysis of distinct morphotypes as exemplified in this study is a promising approach for the discovery of bioactive natural products and pathways of diversification.

AB - Morphotype switches frequently occur in Actinobacteria and are often associated with disparate natural product production. Here, we report on differences in the secondary metabolomes of two morphotypes of a Streptomyces species, including the discovery of a novel antimicrobial glycosylated macrolide, which we named termidomycin A. While exhibiting an unusual 46-member polyene backbone, termidomycin A (1) shares structural features with the clinically important antifungal agents amphotericin B and nystatin A1. Genomic analyses revealed a biosynthetic gene cluster encoding for a putative giant type I polyketide synthase (PKS), whose domain structure allowed us to propose the relative configuration of the 46-member macrolide. The architecture of the biosynthetic gene cluster was different in both morphotypes, thus leading to diversification of the product spectrum. Given the high frequency of genomic rearrangements in Streptomycetes, the metabolic analysis of distinct morphotypes as exemplified in this study is a promising approach for the discovery of bioactive natural products and pathways of diversification.

U2 - 10.1021/acschembio.1c00357

DO - 10.1021/acschembio.1c00357

M3 - Journal article

C2 - 34275291

AN - SCOPUS:85111598707

VL - 16

SP - 1482

EP - 1492

JO - A C S Chemical Biology

JF - A C S Chemical Biology

SN - 1554-8929

IS - 8

ER -