Genome mining of virulent small molecules in human fungal pathogens

The incidence of invasive fungal infections has been increasing at an alarming rate in recent years due to the expanding population of immunocompromised patients as a result of HIV, cancer chemotherapy, and the increasing use of immunosuppressive drugs in organ transplantation and in the treatment of various autoimmune diseases. A major concern is the increasing infections caused by opportunistic fungi, which are resistant or tolerant to clinically available antifungal drugs.

The fungal pathogens are thought to release virulence factors, enzymes and toxins into the host during infection. Some of these virulence factors or toxins are small molecules known as secondary metabolites. At the same time, the fungal secondary metabolites include important clinical drugs such as the antibiotic penicillins, the cholesterol-lowering statins, the immunosuppressive cyclosporin, and the antifungals echinocandins, which have positively impact human health.

Genome sequencing has revealed a large number of gene clusters encoding unknown secondary metabolite biosynthetic pathways in fungal human pathogens. What are the biological targets of these secondary metabolites? Could they be involved in virulence or fungal-host interactions? Could these small molecules be repurposed as drugs?

Our research group is interested in using functional genomics to identify candidate gene clusters in the fungal pathogens that may encode for secondary metabolites important for their pathogenic lifestyle. Using the synthetic biology platforms available in the lab, we attempt to produce the small molecules encode by these gene clusters for chemical and biological characterisations. Understanding the contribution of these small molecules in causing fungal diseases could result in new strategies for novel diagnostics and therapeutics that facilitate early detection and treatment. Furthermore, these bioactive small molecules that target the human macromolecules may be repurposed as novel drugs.

For more background information, see the suggested readings below.