Discovery of the Tiancilactone Antibiotics by Genome Mining of Atypical Bacterial Type II Diterpene Synthases

Liao-Bin Dong; Jeffrey D Rudolf; Ming-Rong Deng; Xiaohui Yan; Ben Shen

doi:10.1002/cbic.201800285

Discovery of the Tiancilactone Antibiotics by Genome Mining of Atypical Bacterial Type II Diterpene Synthases

Chembiochem. 2018 May 27:10.1002/cbic.201800285. doi: 10.1002/cbic.201800285. Online ahead of print.

Authors

Liao-Bin Dong¹, Jeffrey D Rudolf¹, Ming-Rong Deng¹, Xiaohui Yan¹, Ben Shen^{1

2}

Affiliations

¹ Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA.
² Department of Molecular Medicine, Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL, 33458, USA.

Abstract

Although genome mining has advanced the identification, discovery, and study of microbial natural products, the discovery of bacterial diterpenoids continues to lag behind. Herein, we report the identification of 66 putative producers of novel bacterial diterpenoids, and the discovery of the tiancilactone (TNL) family of antibiotics, by genome mining of type II diterpene synthases that do not possess the canonical DXDD motif. The TNLs, which are broad-spectrum antibiotics with moderate activities, are produced by both Streptomyces sp. CB03234 and Streptomyces sp. CB03238 and feature a highly functionalized diterpenoid skeleton that is further decorated with chloroanthranilate and γ-butyrolactone moieties. Genetic manipulation of the tnl gene cluster resulted in TNL congeners, which provided insights into their biosynthesis and structure-activity relationships. This work highlights the biosynthetic potential that bacteria possess to produce diterpenoids and should inspire continued efforts to discover terpenoid natural products from bacteria.

Keywords: antibiotics; biosynthesis; genomics; natural products; terpenoids.

Abstract

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