Grant: Discovery Grants Program - Individual

The growing emergence of microbial strains that are resistant to currently used antibiotic agents is a major threat to human health as resistance to all of the major classes of antibiotics currently in clinical use has already been observed. Pan-resistant pathogens are increasingly being discovered and current forecasts predict that broad-scale ineffectiveness of antimicrobial agents is imminent. The discovery of novel natural products provides unparalleled access to unprecedented molecular scaffolds and unique molecular structures with desirable bioactivities and potencies that are unavailable through rational and combinatorial synthetic strategies. My research program focuses on the isolation of biologically active natural products that exhibit activity against pathogenic microbes, and consequently have significant potential as lead compounds for the development of new therapeutics for infectious disease. We focus on natural products produced by endophytic fungi of terrestrial, marine and freshwater plants, and a library of about 500 fungal endophyte cultures, many of which could represent new fungal species, is currently under investigation. Additional endophytic strains are continuously being isolated to increase our collection and we will also ferment fungi in co-culture with other fungi and bacteria and under various biological and chemical conditions to trigger cryptic biosynthetic genes and maximise the chemical diversity of our collection. My group has developed simple, robust and effective bioactivity and metabolomic profiling procedures that we will be applying in our search for novel molecular scaffolds. Fungal extracts will be evaluated in a suite of bioassays to assess their inhibitory effects against pathogenic microorganisms and their ability to modulate efflux pumps within these pathogens. This will allow us to compile bioactivity profiles for the extracts that can be related to the modes-of-action of their antibiotic constituents in an effort to discover new antibiotic classes and also identify natural products that can be used to increase the effectiveness of our current antibiotics by remediating for the effects of drug resistance. In conjunction with the compilation of the bioactivity profiles, NMR and LC-MS based metabolomics approaches will be used to dereplicate extracts that contain known antibiotics and prioritise projects for further investigation. Extracts that exhibit promising bioactivity profiles and unique metabolomic signatures will be subjected to bioassay-guided fractionation to isolate and identify the active components. The modes-of-action of the novel natural products that are isolated will then be probed by genomics, proteomics and chemical genetics. My research will ultimately lead to the discovery of lead compounds from the extensive biodiversity provided by fungal endophytes for the development of new therapeutics to fight infectious disease.