Understanding the chemical warfare of actinomycetes as keystone bacterial species for accelerated antibiotic discovery

Two thirds of clinically used antibiotics are produced by the bacterial order, actinomycetes, thus they are fundamental to the fight against antimicrobial resistant infections.1 Genome sequencing of these biotechnologically relevant strains has revealed the considerable genetic potential of actinomycetes, as they contain a rich reservoir of biosynthetic gene clusters (the blueprint to produce many more specialized metabolites).2 Even the genomes of well-studied actinomycetes contain genes that encode many more metabolites with drug potential than we previously thought. These cryptic gene clusters provide an exciting opportunity for the discovery of novel antibiotics to combat antimicrobial resistance. This studentship will assess actinomycetes as ‘keystone species’ within the environment. Keystone species have a disproportionately large effect on their environment, relative to their abundance. Actinomycetes have large genomes encompassing many known and cryptic biosynthetic gene clusters. Therefore, actinomycete secondary metabolomes may have a disproportionately large effect on their environment, relative to their low abundance in nature (typically <1% of microbial communities). Understanding the factors involved in the induction of these cryptic biosynthetic gene clusters is paramount for eliciting novel chemistry. Bacterial interactions underpin strain survival, population dynamics and the establishment of ecological niches.3 These complex relationships are communicated through a constant source of chemical warfare and metabolite exchange. Yet despite this wealth of induced chemical potential, the mechanisms are poorly understood. Recent advances in mass spectrometry can now allow us to understand the chemicals involved in underpinning these complex chemical exchanges. Mass spectrometry imaging (MSI) allows visualization of compounds involved in microbial interactions in real time.4 Additionally, global natural products social (GNPS) molecular networking allows rapid chemical dereplication based on chemical architecture, thus enabling new chemistry to be prioritised.5 Using these cutting-edge approaches to harnessing natural microbial chemical warfare for biomedical applications provides an exciting opportunity for natural products drug discovery.