Resistance and phylogeny guided discovery reveals structural novelty of tetracycline antibiotics.
Ling Yu Li, Yi Ling Hu, Jia Lin Sun, Long Bo Yu, Jing Shi, Zi Ru Wang, Zhi Kai Guo, Bo Zhang, Wen Jie Guo, Ren Xiang Tan, Hui Ming Ge
Author Information
Ling Yu Li: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn.
Yi Ling Hu: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn.
Jia Lin Sun: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn.
Long Bo Yu: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn.
Jing Shi: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn.
Zi Ru Wang: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn.
Zhi Kai Guo: Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture, Institute of Tropical Bioscience and Bio-technology, Chinese Academy of Tropical Agricultural Sciences Haikou 571101 China.
Bo Zhang: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn.
Wen Jie Guo: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn.
Ren Xiang Tan: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn. ORCID
Hui Ming Ge: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University Nanjing 210023 China rxtan@nju.edu.cn hmge@nju.edu.cn. ORCID
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.
References
Nat Chem Biol. 2011 Dec 18;8(2):154-61
[PMID: 22179067]
RSC Chem Biol. 2021 Feb 2;2(2):556-567
[PMID: 34458799]
