Resistance and phylogeny guided discovery reveals structural novelty of tetracycline antibiotics. Issue 43 (27th October 2022)

• Record Type: Journal Article
• Authors: Li, Ling Yu; Hu, Yi Ling; Sun, Jia Lin; Yu, Long Bo; Shi, Jing; Wang, Zi Ru; Guo, Zhi Kai; Zhang, Bo; Guo, Wen Jie; Tan, Ren Xiang; Ge, Hui Ming
• Is Part Of: Chemical science. Volume 13:Issue 43(2022)
• Page Start: 12892
• Page End: 12898
• Publication Date: 2022-10-27
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d2sc03965f
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Using resistance gene genome mining strategy and refinement with chain length factor, we obtained 25 distinct tetracycline biosynthetic gene clusters and a novel tetracycline. The biosynthesis of the highly modified tetracycline was investigated. Abstract : Tetracyclines are a class of antibiotics that exhibited potent activity against a wide range of Gram-positive and Gram-negative bacteria, yet only five members were isolated from actinobacteria, with two of them approved as clinical drugs. In this work, we developed a genome mining strategy using a TetR/MarR-transporter, a pair of common resistance enzymes in tetracycline biosynthesis, as probes to find the potential tetracycline gene clusters in the actinobacteria genome database. Further refinement using the phylogenetic analysis of chain length factors resulted in the discovery of 25 distinct tetracycline gene clusters, which finally resulted in the isolation and characterization of a novel tetracycline, hainancycline (1 ). Through genetic and biochemical studies, we elucidated the biosynthetic pathway of 1, which involves a complex glycosylation process. Our work discloses nature's huge capacity to generate diverse tetracyclines and expands the chemical diversity of tetracyclines.