In this research project, we aim to identify and develop promising natural products from actinomycetes that can modulate (inhibit or promote) the growth of mammalian cells.

Actinomycetes as a source of natural products

The actinomycetes are a diverse family of filamentous bacteria that produce a wealth of secondary metabolites, such as antibiotics, anticancer, antifungal, and immunosuppressant compounds. The aim of the proposal is to set up a novel pipeline for the screening of actinomycetes of the Leiden University strain collection on surface-grown cultures, for bioactive compounds that modulate the growth of mammalian cells.

Objectives

The key objectives are:

(1) engineering of novel cultivation systems that allow direct diffusion of molecules from surface-grown cultures into mammalian cell cultures, through size-selective microfilters, and study their effect on cell proliferation;

(2) identifying eliciting molecules that activate the expression of silent BGCs specifying growth-modulating compounds, with focus on host-derived signals and the response of actinomycetes to cancer cell lines; and

(3) harness the technologies developed under (1) and (2) to express, isolate and identify the actinomycete-derived bioactive compounds.

Lead identification and development

Compounds will be assessed for their ability to either promote growth of CHO cells, aimed at higher cell titres in industrial production systems, or to inhibit the growth of cancer cells, for which we use pancreatic cancer cells and organoids as the model systems. Once promising producer strains have been identified, we will use a pancreatic organ-on-a-chip cancer model for further analysis of the most promising molecules and for mode of action studies.

• actinomycetes
• bioactive molecules
• biotechnology
• microbiology