PhD defence

Expanding the chemical space of antibiotics produced by Paenibacillus and Streptomyces

• N.V. Machushynets

Date

Thursday 5 September 2024

Time

13:00 - 14:00 hour

Address

Academy Building
Rapenburg 73
2311 GJ Leiden

Supervisor(s)

• Prof.dr. G.P. van Wezel
• Prof.dr. N.I. Martin

Samenvatting

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 has 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.

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 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.

PhD dissertations

Approximately one week after the defence, PhD dissertations by Leiden PhD students are available digitally through the Leiden Repository, that offers free access to these PhD dissertations. Please note that in some cases a dissertation may be under embargo temporarily and access to its full-text version will only be granted later.

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