Research Projects

http://www.science.uwa.edu.au/courses/postgrad/opportunities/chemistry/metabolites

Fungi 
are prolific producers of bioactive small molecules known as secondary metabolites. These fungal secondary metabolites have been the source of medicine and include important clinical drugs, such as the antibiotic penicillin and the cholesterol-Fungi are a major cause of plant diseases and have a significant economic impact on crop production. Several secondary metabolites produced by some fungal pathogens are known to enable them to cause diseases on plants e.g. HC-toxin, T-toxin and victorin. Genome sequencing has revealed a large number of gene clusters encoding secondary metabolite biosynthetic pathways in fungal plant pathogens. However, majority of these secondary metabolite pathways are uncharacterised, including those infecting important crops in Australia (e.g. wheat). 
What are the functions of these yet-to-be revealed secondary metabolites? Could they be involved in virulence or fungal-host interactions?

    Our research group is interested in using functional genomics to identify candidate gene clusters in the fungal pathogens that may encode secondary metabolites important for their pathogenic lifestyle. The current focus is on wheat pathogens including Parastagonospora nodorum and Zymoseptoria tritici. 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. 

Identification and characterisation of the secondary metabolites produced by the fungal pathogens during host infection could provide insights into the mechanism of the diseases and could result in new disease control strategies. Furthermore, these bioactive small molecules that target the plant hosts may be repurposed as novel herbicides.

This project is currently funded by an ARC Discovery Early Career Researcher Fellowship to Yit Heng Chooi.

For more information about postgraduate (PhD, Hons) research opportunities please see: 

Student enquiries with CV are welcome.

Suggested reading:

1) Chooi Y-H and Solomon PS (2014) A chemical ecogenomics approach to understand the roles of secondary metabolites in fungal cereal pathogens. Front. Microbiol. 5:640. http://dx.doi.org/10.3389/fmicb.2014.00640

2) Chooi YH, Krill C, Barrow RA, Chen S, Trengove R, Oliver RP, Solomon PS (2015) An in planta-expressed polyketide synthase produces (R)-mellein in the wheat pathogen Parastagonospora nodorum. Appl Environ Microbiol. 81(1):177-86. http://dx.doi.org/10.1128/AEM.02745-14

3) Chooi Y-H, Muria-Gonzalez MJ, Mead, OL and Solomon PS (2015) SnPKS19 encodes the polyketide synthase for alternariol mycotoxin biosynthesis in the wheat pathogen Parastagonospora nodorum. Appl Environ Microbiol. http://dx.doi.org/10.1128/AEM.00278-15

4) Chooi YH, Muria-Gonzalez MJ, Solomon PS (2014) A genome-wide survey of the secondary metabolite biosynthesis genes in the wheat pathogen Parastagonospora nodorum. Mycology 5(3):192-206. http://dx.doi.org/10.1080/21501203.2014.928386

5) Möbius N, Hertweck C (2009) Fungal phytotoxins as mediators of virulence. Curr Opin Plant Biol. http://dx.doi.org/10.1016/j.pbi.2009.06.004

6) Scharf DH1, Heinekamp T1, Brakhage AA (2014) Human and plant fungal pathogens: the role of secondary metabolites. PLoS Pathog. 10(1): e1003859. http://dx.doi.org/10.1371/journal.ppat.1003859


Synthetic biology tools for biosynthesis of small molecules


Fungi are prolific producers of bioactive small molecules known as secondary metabolites. These fungal secondary metabolites have been the source of medicines, including life-saving drugs, such as the antibiotic penicillin and the cholesterol-lowering statins. Recent genome sequencing efforts have revealed a large number of gene clusters encoding unknown secondary metabolite biosynthetic pathways in fungi. Thus, there are immense opportunities for discovery of novel molecules from these sequenced fungal genomes for application in medicine and agriculture.

    At the same time, there are increasing interests in engineering microbes as chemical factories for sustainable production of pharmaceutical drugs, fine chemicals and fuels. This will involve construction of new pathway consisted of multiple genes in the microbial cells and optimizing the gene expression to maximize production.  The production of secondary metabolites in fungi involves orchestrating the expression of multiple genes encoding various biosynthetic enzymes, often in response to specific environmental signals. The translated biosynthetic enzymes then come together to catalyse a series of biochemical reactions required to make the desired molecules.

Can we learn from fungi to develop better tools for engineering microbes?

    This project aims to hijack the genetic circuits of fungal secondary metabolite pathways as tools for engineering eukaryotic cells (yeast and filamentous fungi) for production of useful chemicals and for discovery of novel molecules from fungal genomes.

    Another aspect of interest in secondary metabolite biosynthesis is chemical diversification. Microbes recombined and evolved genes from different pathways to expand the chemical diversity. Understanding the evolution of fungal secondary metabolite pathways may lead to new insights that are useful for generating chimeric or artificial biosynthetic pathways. This ultimate aim is to generate novel analogs of potential drug leads by metabolic pathway engineering.

For more information about postgraduate (PhD, Hons) research opportunities please see: 

Student enquiries with CV are welcome.

Suggested reading:

1) Chooi Y-H and Solomon PS (2014) A chemical ecogenomics approach to understand the roles of secondary metabolites in fungal cereal pathogens. Front. Microbiol. 5:640. http://dx.doi.org/10.3389/fmicb.2014.00640

2) Cacho RA, Tang Y, Chooi YH (2015) Next-generation sequencing approach for connecting secondary metabolites to biosynthetic gene clusters in fungi. Front. Microbiol. 5:774. http://dx.doi.org/10.3389/fmicb.2014.00774

3) Keller NP (2015) Translating biosynthetic gene clusters into fungal armor and weaponry. Nat. Chem. Biol.,11:671 http://dx.doi.org/10.1038/NCHEMBIO.1897 

4) Mattern DJ, Valiante V, Unkles SE, Brakhage AA (2015) Synthetic biology of fungal natural products. Front. Microbiol. 6:775. http://dx.doi.org/10.3389/fmicb.2015.00775

5) Lazarus CM, Williams K, Bailey AM (2014) Reconstructing fungal natural product biosynthetic pathway. Nat Prod Rep. http://dx.doi.org/10.1039/c4np00084f

6) Winter JM, Tang Y (2012) Synthetic biological approaches to natural product biosynthesis. Curr Opin Biotechnol 23(5):736-43. http://dx.doi.org/10.1016/j.copbio.2011.12.016

7) Chooi Y-H, Tang Y (2012) Navigating the fungal polyketide chemical space: from genes to molecules, J Org Chem 77(22), 9933-53. http://dx.doi.org/10.1021/jo301592k

8) Medema MH, Breitling R, Bovenberg R, Takano, E (2011) Exploiting plug-and-play synthetic biology for drug discovery and production in microorganisms. Nat Rev Microbiol 9:131-37. http://dx.doi.org/10.1038/nrmicro2478



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 information about postgraduate (PhD, Hons) research opportunities please see: 

Student enquiries with CV are welcome.

Suggested reading:

1) Scharf DH, Heinekamp T, Brakhage AA (2014) Human and Plant Fungal Pathogens: The Role of Secondary Metabolites. PLoS Pathog. 10(1): e1003859.http://dx.doi.org/10.1371/journal.ppat.1003859

2) Chooi YH, Fang JX, Liu H, Filler SG, Wang P, Tang Y (2013) Genome Mining of a Prenylated and Immunosuppressive Polyketide from Pathogenic Fungi. Org Lett.; 15(4):780-783. http://dx.doi.org/10.1021/ol303435y

3) Yin WB, Chooi YH, Smith AR, Cacho RA, Hu YC, White TC, Tang Y. Discovery of Cryptic Polyketide Metabolites from Dermatophytes Using Heterologous Expression in Aspergillus nidulans. ACS Synth Biol. 2013; 2(11):629-634.http://dx.doi.org/10.1021/sb400048b

4) Garvey GS, Keller NP. Fungal secondary metabolites and their fundamental roles in human mycoses. Curr Fung Infect Rep. 4(4), 256-265.http://dx.doi.org/10.1007/s12281-010-0032-8