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Health Sciences profile

Associate Professor Brian Monk

PositionAssociate Professor
DepartmentDepartment of Oral Sciences
QualificationsBSc(Hons)(Well) PhD(Monash)
Research summaryMolecular 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

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

Niimi, K., Harding, D. R. K., Holmes, A. R., Lamping, E., Niimi, M., Tyndall, J. D. A., Cannon, R. D., & Monk, B. C. (2012). Specific interactions between the Candida albicans ABC transporter Cdr1p ectodomain and a D-octapeptide derivative inhibitor. Molecular Microbiology, 85(4), 747-767. doi: 10.1111/j.1365-2958.2012.08140.x

Monk, B. C., & Goffeau, A. (2008). Outwitting multidrug resistance to antifungals. Science, 321(5887), 367-369.

Lamping, E., Monk, B. C., Niimi, K., Holmes, A. R., Tsao, S., Tanabe, K., Niimi, M., … Cannon, R. D. (2007). Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryotic Cell, 6(7), 1150-1165.

Journal - Research Article

Aung, H. L., Samaranayaka, C. U. K., Enright, R., Beggs, K. T., & Monk, B. C. (2015). Characterisation of the DNA gyrase from the thermophilic eubacterium Thermus thermophilus. Protein Expression & Purification, 107, 62-67. doi: 10.1016/j.pep.2014.11.009

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

Keniya, M. V., Fleischer, E., Klinger, A., Cannon, R. D., & Monk, B. C. (2015). Inhibitors of the Candida albicans Major Facilitator Superfamily transporter Mdr1p responsible for fluconazole resistance. PLoS ONE, e0126350. doi: 10.1371/journal.pone.0126350

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

Keniya, M. V., Cannon, R. D., Nguyễn, Ấ., Tyndall, J. D. A., & Monk, B. C. (2013). Heterologous expression of Candida albicans Pma1p in Saccharomyces cerevisiae. FEMS Yeast Research, 13(3), 302-311. doi: 10.1111/1567-1364.12035

Shankar, M., Wilbanks, S. M., Nakatani, Y., Monk, B. C., & Tyndall, J. D. A. (2013). Catalysis product captured in lumazine synthase from the fungal pathogen Candida glabrata. Acta Crystallographica Section D, 69(8), 1580-1586. doi: 10.1107/S0907444913010949

Monk, B. C. (2013). Transporters: A yeast ABC interactome primer. Nature Chemical Biology, 9(9), 531-533. doi: 10.1038/nchembio.1317

Rawal, M. K., Khan, M. F., Kapoor, K., Goyal, N., Sen, S., Saxena, A. K., … Tyndall, J. D. A., Monk, B. C., Cannon, R. D., … Prasad, R. (2013). Insight into pleiotropic drug resistance ATP-binding cassette pump drug transport through mutagenesis of Cdr1p transmembrane domains. Journal of Biological Chemistry, 288(34), 24480-24493. doi: 10.1074/jbc.M113.488353

Niimi, K., Woods, M. A., Maki, K., Nakayama, H., Hatakenaka, K., Chibana, H., … Niimi, M., Cannon, R. D., & Monk, B. C. (2012). Reconstitution of high-level micafungin resistance detected in a clinical isolate of Candida glabrata identifies functional homozygosity in glucan synthase gene expression. Journal of Antimicrobial Chemotherapy, 67(7), 1666-1676. doi: 10.1093/jac/dks112

Niimi, K., Harding, D. R. K., Holmes, A. R., Lamping, E., Niimi, M., Tyndall, J. D. A., Cannon, R. D., & Monk, B. C. (2012). Specific interactions between the Candida albicans ABC transporter Cdr1p ectodomain and a D-octapeptide derivative inhibitor. Molecular Microbiology, 85(4), 747-767. doi: 10.1111/j.1365-2958.2012.08140.x

Hayama, K., Ishibashi, H., Ishijima, S. A., Niimi, K., Tansho, S., Ono, Y., Monk, B. C., Holmes, A. R., … Cannon, R. D., & Abe, S. (2012). A D-octapeptide drug efflux pump inhibitor acts synergistically with azoles in a murine oral candidiasis infection model. FEMS Microbiology Letters, 328(2), 130-137. doi: 10.1111/j.1574-6968.2011.02490.x

Tanabe, K., Lamping, E., Nagi, M., Okawada, A., Holmes, A. R., Miyazaki, Y., Cannon, R. D., Monk, B. C., & Niimi, M. (2011). Chimeras of Candida albicans Cdr1p and Cdr2p reveal features of pleiotropic drug resistance transporter structure and function. Molecular Microbiology, 82(2), 416-433. doi: 10.1111/j.1365-2958.2011.07820.x

Holmes, A. R., Keniya, M. V., Ivnitski-Steele, I., Monk, B. C., Lamping, E., Sklar, L. A., & Cannon, R. D. (2011). The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates. Antimicrobial Agents & Chemotherapy, 56(3), 1508-1515. doi: 10.1128/aac.05706-11

Lamping, E., Baret, P. V., Holmes, A. R., Monk, B. C., Goffeau, A., & Cannon, R. D. (2010). Fungal PDR transporters: Phylogeny, topology, motifs and function. Fungal Genetics & Biology, 47(2), 127-142. doi: 10.1016/j.fgb.2009.10.007

Farah, R. A., Monk, B. C., Swain, M. V., & Drummond, B. K. (2010). Protein content of molar-incisor hypomineralisation enamel. Journal of Dentistry, 38, 591-596. doi: 10.1016/j.jdent.2010.04.012

Niimi, K., Monk, B. C., Hirai, A., Hatakenaka, K., Umeyama, T., Lamping, E., … Cannon, R. D., & Niimi, M. (2010). Clinically significant micafungin resistance in Candida albicans involves modification of a glucan synthase catalytic subunit GSC1 (FKS1) allele followed by loss of heterozygosity. Journal of Antimicrobial Chemotherapy, 65, 842-852. doi: 10.1093/jac/dkq073

Cannon, R. D., Lamping, E., Holmes, A. R., Niimi, K., Baret, P. V., Keniya, M. V., … Niimi, M., … Monk, B. C. (2009). Efflux-mediated antifungal drug resistance. Clinical Microbiology Reviews, 22(2), 291-321. doi: 10.1128/cmr.00051-08

Ivnitski-Steele, I., Holmes, A. R., Lamping, E., Monk, B. C., Cannon, R. D., & Sklar, L. A. (2009). Identification of Nile red as a fluorescent substrate of the Candida albicans ATP-binding cassette transporters Cdr1p and Cdr2p and the major facilitator superfamily transporter Mdr1p. Analytical Biochemistry, 394(1), 87-91. doi: 10.1016/j.ab.2009.07.001

Holmes, A. R., Lin, Y.-H., Niimi, K., Lamping, E., Keniya, M., Niimi, M., … Monk, B. C., & Cannon, R. D. (2008). ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates. Antimicrobial Agents & Chemotherapy, 52(11), 3851-3862. doi: 10.1128/AAC.00463-08

Monk, B. C., & Goffeau, A. (2008). Outwitting multidrug resistance to antifungals. Science, 321(5887), 367-369.

Lamping, E., Monk, B. C., Niimi, K., Holmes, A. R., Tsao, S., Tanabe, K., Niimi, M., … Cannon, R. D. (2007). Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryotic Cell, 6(7), 1150-1165.

Cannon, R. D., Lamping, E., Holmes, A. R., Niimi, K., Tanabe, K., & Monk, B. C. (2007). Candida albicans drug resistance: Another way to cope with stress. Microbiology, 153, 3211-3217.

Niimi, K., Maki, K., Ikeda, F., Holmes, A. R., Lamping, E., Niimi, M., Monk, B. C., & Cannon, R. D. (2006). Overexpression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility. Antimicrobial Agents & Chemotherapy, 50(4), 1148-1155.

Holmes, A. R., Tsao, S., Ong, S.-W., Lamping, E., Niimi, K., Monk, B. C., Niimi, M., … Cannon, R. D. (2006). Heterozygosity and functional allelic variation in the Candida albicans efflux pump genes CDR1 and CDR2. Molecular Microbiology, 62(1), 170-186.

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Journal - Research Other

Holmes, A. R., Tsao, S., Lamping, E., Niimi, K., Monk, B. C., Tanabe, K., Niimi, M., & Cannon, R. D. (2006). Amino acid residues affecting drug pump function in Candida albicans: C. albicans drug pump function [Review]. Japanese Journal of Medical Mycology / Nippon Ishinkin Gakkai Zasshi, 47(4), 275-281.

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