Metabolomics Tools Assisting Classic Screening Methods in Discovering New Antibiotics from Mangrove Actinomycetia in Leizhou Peninsula
Qin-Pei Lu,
Yong-Mei Huang,
Shao-Wei Liu,
Gang Wu,
Qin Yang,
Li-Fang Liu,
Hai-Tao Zhang,
Yi Qi,
Ting Wang,
Zhong-Ke Jiang,
Jun-Jie Li,
Hao Cai,
Xiu-Jun Liu,
Hui Luo,
Cheng-Hang Sun
Affiliations
Qin-Pei Lu
Department of Microbial Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Yong-Mei Huang
The Key Lab of Zhanjiang for R&D Marine Microbial Resources in the Beibu Gulf Rim, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
Shao-Wei Liu
Department of Microbial Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Gang Wu
Department of Microbial Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Qin Yang
Department of Microbial Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Li-Fang Liu
Department of Microbial Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Hai-Tao Zhang
The Key Lab of Zhanjiang for R&D Marine Microbial Resources in the Beibu Gulf Rim, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
Yi Qi
The Key Lab of Zhanjiang for R&D Marine Microbial Resources in the Beibu Gulf Rim, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
Ting Wang
Department of Microbial Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Zhong-Ke Jiang
Department of Microbial Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Jun-Jie Li
The Key Lab of Zhanjiang for R&D Marine Microbial Resources in the Beibu Gulf Rim, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
Hao Cai
Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Xiu-Jun Liu
Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Hui Luo
The Key Lab of Zhanjiang for R&D Marine Microbial Resources in the Beibu Gulf Rim, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
Cheng-Hang Sun
Department of Microbial Chemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Mangrove actinomycetia are considered one of the promising sources for discovering novel biologically active compounds. Traditional bioactivity- and/or taxonomy-based methods are inefficient and usually result in the re-discovery of known metabolites. Thus, improving selection efficiency among strain candidates is of interest especially in the early stage of the antibiotic discovery program. In this study, an integrated strategy of combining phylogenetic data and bioactivity tests with a metabolomics-based dereplication approach was applied to fast track the selection process. A total of 521 actinomycetial strains affiliated to 40 genera in 23 families were isolated from 13 different mangrove soil samples by the culture-dependent method. A total of 179 strains affiliated to 40 different genera with a unique colony morphology were selected to evaluate antibacterial activity against 12 indicator bacteria. Of the 179 tested isolates, 47 showed activities against at least one of the tested pathogens. Analysis of 23 out of 47 active isolates using UPLC-HRMS-PCA revealed six outliers. Further analysis using the OPLS-DA model identified five compounds from two outliers contributing to the bioactivity against drug-sensitive A. baumannii. Molecular networking was used to determine the relationship of significant metabolites in six outliers and to find their potentially new congeners. Finally, two Streptomyces strains (M22, H37) producing potentially new compounds were rapidly prioritized on the basis of their distinct chemistry profiles, dereplication results, and antibacterial activities, as well as taxonomical information. Two new trioxacarcins with keto-reduced trioxacarcinose B, gutingimycin B (16) and trioxacarcin G (20), together with known gutingimycin (12), were isolated from the scale-up fermentation broth of Streptomyces sp. M22. Our study demonstrated that metabolomics tools could greatly assist classic antibiotic discovery methods in strain prioritization to improve efficiency in discovering novel antibiotics from those highly productive and rich diversity ecosystems.
