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Honorary Associate Professor Brian Monk

Contact Details

Phone
64 3 479 7099
Email
brian.monk@otago.ac.nz

University Links

Position
Associate Professor
Department
Department of Oral Sciences
Qualifications
BSc(Hons)(Well) PhD(Monash)
Research summary
Molecular microbiology

Research

It is imperative that new ways are discovered to combat infectious disease, especially where clinically significant drug resistance has emerged. Dr Monk uses molecular genetic manipulation of yeast and bacterial systems to express drug targets for effective screening of compound libraries. Most of the antifungal targets he has developed are membrane proteins. These include essential P-type ATPases, fungal glucan synthase, cytochrome P450 enzymes and drug efflux pumps. Other targets include fungal transcription factors and enzymes involved in fungal riboflavin biosynthesis. For example, we recently determined the X-ray structure of the riboflavin biosynthetic enzyme lumazine synthase from the fungal pathogen Candida glabrata. The challenge of obtaining monodisperse membrane proteins for structurally resolution by X-ray crystallography is well advanced. The structure of yeast lanosterol 14α-demethylase has been determined and other targets of interest are in crystal trials. The yeast expression system patented by Dr Monk in 2003 is used widely to express membrane proteins from a range of sources including pathogenic fungi, plants, and humans. Related research interests include defining and overcoming mechanisms of echinocandin, anthelmintic and antimalarial resistance, expressing human drug targets for drug screening, and equipping yeast biofactories with efflux pumps to improve productivity by protecting against toxic substrates, products, and metabolites.

Publications

Monk, B. C., Tomasiak, T. M., Keniya, M. V., Huschmann, F. U., Tyndall, J. D. A., O'Connell, III, J. D., Cannon, R. D., … Stroud, R. M. (2014). Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer. PNAS, 111(10), 3865-3870. doi: 10.1073/pnas.1324245111 Journal - Research Article

Sagatova, A. A., Keniya, M. V., Wilson, R. K., Monk, B. C., & Tyndall, J. D. A. (2015). Structural insights into binding of the antifungal drug fluconazole to Saccharomyces cerevisiae lanosterol 14α-demethylase. Antimicrobial Agents & Chemotherapy, 59(8), 4982-4989. doi: 10.1128/aac.00925-15 Journal - Research Article

Sagatova, A. A., Keniya, M. V., Wilson, R. K., Sabherwal, M., Tyndall, J. D. A., & Monk, B. C. (2016). Triazole resistance mediated by mutations of a conserved active site tyrosine in fungal lanosterol 14α-demethylase. Scientific Reports, 6, 26213. doi: 10.1038/srep26213 Journal - Research Article

Sagatova, A. A., Keniya, M. V., Tyndall, J. D. A., & Monk, B. C. (2018). The impact of homologous resistance mutations from pathogenic yeast on Saccharomyces cerevisiae lanosterol 14α-demethylase. Antimicrobial Agents & Chemotherapy, 62(3), e02242-17. doi: 10.1128/aac.02242-17 Journal - Research Article

Tyndall, J. D. A., Sabherwal, M., Sagatova, A. A., Keniya, M. V., Negroni, J., Wilson, R. K., Woods, M. A., … Monk, B. C. (2016). Structural and functional elucidation of yeast lanosterol 14α-demethylase in complex with agrochemical antifungals. PLoS ONE, 11(12), e0167485. doi: 10.1371/journal.pone.0167485 Journal - Research Article

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