Proefschrift
Expanding the chemical space of antibiotics produced by Paenibacillus and Streptomyces
Antibiotic-resistant bacteria pose a major health threat. Addressing this challenge requires among others the development of new antibacterial compounds. The research described in this thesis focuses on discovering novel antibiotics from soil bacteria, specifically Streptomyces and Paenibacillus.Despite the vast potential encoded within bacterial genomes, only a fraction of the natural products have been explored experimentally. A critical obstacle in antibiotic discovery is the repeated rediscovery of known compounds, a process called replication. This underscores the urgent need for innovative strategies in antibiotic discovery to uncover new chemical entities effectively.
- Auteur
- N.V. Machushynets
- Datum
- 05 september 2024
- Links
- Thesis in Leiden Repository
To overcome this challenge we developed an efficient analytical platform called nanoRAPIDS, designed for the discovery and dereplication of low-abundance bioactive compounds through at-line nanofractionation, molecular networking, and bioactivity assays. nanoRAPIDS platform was successfully applied to analyze the bioactive crude extracts of Bacillus and Streptomyces and highlighting the individual mass features that contribute to the activity in the crude extract.
Advanced spectroscopic techniques such as LC-MS-based metabolomics, molecular networking, and nanofractionation enabled the detection and characterization of antibiotics in complex bacterial extracts. Synthetic chemistry and bioinformatics allowed the discovery, optimization, and refinement of the antibacterial properties of compounds of interest. Key discoveries included tridecaptin Oct-His9 effective against colistin-resistant Pseudomonas aeruginosa, and paenitracin bioactive against vancomycin-resistant Enterococcus faecium. Other novel compounds identified included paenilipoheptins, quinazolinones, actinomycin L, and tridecaptin lipopeptides.
The research described in this thesis uses a wide range of computational, biological, and analytical chemical approaches to activate cryptic biosynthetic pathways and find new chemistry, thus contributing to the need for new chemical space as the basis for our future antibiotics. The findings highlight that there still is a lot of potential in soil bacteria as sources of novel antibiotics, to aid us in the continuing combat against multi-resistant bacterial infections.