New antibiotics are urgently needed to combat persistent, emerging and re-emerging infectious diseases. Historically, microbial natural products have been a prolific source of antibacterials, and the screening of microbial extracts has yielded many classes of antibiotics. However, this approach was largely abandoned by big pharma because of the high rates of rediscovery of known antibiotics, and the general belief that there were very few new antibacterials to be discovered from microbial natural products.
Sequencing of bacterial genomes has changed that view completely. In many bacteria there are far more gene clusters directing the biosynthesis of antibiotic-like metabolites than natural products known to be produced by the organism. These so-called “cryptic” gene clusters (cryptic because their metabolic products are not known) are often silent (not expressed) under standard laboratory conditions, and can represent up to 80-90% of the secondary metabolite gene clusters in some bacteria.
In recent years we have witnessed an increased in the employment of cocultures (i.e. cocultivation of more than 1 microorganism) as a strategy to discover new natural products by exploiting cross-communication processes mediated by diffusible signalling molecules.
In this project we will carry out an in-depth study of the capacity of this strategy to discover new antibacterials from microbial metabolites. Objectives: a) Cocultivation of microorganisms from an actinomycete-based microbe collection employing a specifically designed dual fermentation system. b) Antibiosis screening of the obtained microbial extracts using modern high-throughput technologies; identification of active extracts c) LC-MS based chemical dereplication of active extracts using in-house and external natural product databases; identification of promising extracts d) Scale-up of active extracts, bioactivity-guided fractionation process to purify active compounds; structural elucidation of active compounds
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