The main aim of Dr Monk's research is to develop new anti-infectives, particularly antimicrobial agents, by understanding of the structure and function of accessible membrane proteins at the surface of pathogenic organisms. His group is using combinatorial methods and genetic approaches to synthesise and screen in-house libraries of structural and chemical diversity for compounds that provide the basis for new drugs. These approaches have produced novel, surface-active fungicides directed at the plasma membrane proton pump of yeast and antifungal adjuvants that target an enzyme involved in the evolution of resistance to antifungals. In addition, his laboratory is working towards establishing the structure of the yeast plasma membrane proton pump so that they can ultimately undertake structure-directed drug design. This method will allow the production of even more specific and potent fungicides.

His group has assembled the major technological elements of a drug discovery pipeline. These can now be used to provide a link to practical pharmaceutical development for many targets that are currently being identified from genomics initiatives, molecular genetic studies and biological analysis of pathogenic organisms. In the longer term, the philosophy of targeting the surface of pathogenic organisms will lead to improved anti-infectives that will limit the development of resistant pathogens and avoid unwanted side effects in patients.

Funding

NIH pilot grant (R21), to Dr R.D. Cannon, Dr B.C. Monk and Dr A. Holmes. Combating drug resistance of Candida albicans, 2003-2004

Japan Health Science Foundation, to Dr R.D. Cannon, Dr M. Niimi, Dr K. Niimi, Dr A. Holmes, Dr E. Lamping and Dr B.C. Monk Screening for Candida albicans multidrug efflux pump inhibitors in a D-octapeptide combinatorial library, 2000-2003

Marsden Fund, to BC Monk, JP Dufour and SM Cutfield for a project entitled: ‘Breaking the mould through structural resolution of a prototypic P-type ATPase’, 2000-2001.

Otago Research Grant, to BC Monk, RD Cannon, K Niimi and A Goffeau for a project entitled: ‘D-octapeptide inhibition of multidrug efflux in Saccharomyces and pathogenic Candida’, 2000.

New Zealand Lottery Board, to BC Monk for a project entitled: A screening platform for drug discovery’, 1999-2000.

New Zealand Lottery Board, to BC Monk, K Niimi and RD Cannon for a project entitled: ‘A novel broad-spectrum fungicide that overcomes multi-drug resistance’, 2000.

Selected Publications

Niimi, M., Y. Nagai, K. Niimi, S. Wada, R.D. Cannon, Y. Uehara and B.C. Monk (2002) Identification of two proteins induced by exposure of the pathogenic fungus Candida glabrata to fluconazole. Journal of Chromatography B. 782:245-252.

Monk, B.C., R.D. Cannon, K. Nakamura, M. Niimi, K. Niimi, D.R.K. Harding, A.R. Holmes, E. Lamping, A. Goffeau and A. Decottignies: Membrane protein expression system and its application. International patent application # PCT/NZ02/00163 filed August 23rd 2002.

Decottignies, A., B. Rogers, M. Kowlaczkowski, E. Carvajal, E. Balzi, G. Consiel, K. Niimi, A. Di Pietro, B.C. Monk and A. Goffeau. (2001) The pleiotropic drug ABC transporters from Saccharomyces cerevisiae. In Microbial Multidrug Efflux, pp157-176. Horizon Scientific Press, Wymondham, UK.

Nakamura, K., M. Niimi, K. Niimi, J. Yates, A. Decottignies, B.C. Monk, A., Goffeau and R.D. Cannon (2001) Functional expression of the Candida albicans drug efflux pump in a Saccharomyces cerevisiae strain deficient in membrane transporters. Antimicrob. Agents Chemother. 45, 3366-3374.

Wada, S., M. Niimi, K. Niimi, A.R. Holmes, A. Decottignies, B.C. Monk, A. Goffeau, R.D. Cannon and Y. Uehara . Characterisation of Candida glabrata ABC transporters CgCdr1p and Pdh1p expressed in a Saccharomyces cerevisiae strain deficient in membrane transporters. J. Biol. Chem. 277:46809-21.

Monk, B.C. and R.D. Cannon Genomic pathways to antifungal discovery. Current Drug Targets - Infectious Disorders 2: 309-29.

Niimi, M., R.D. Cannon and B.C. Monk (1999). Candida albicans pathogenicity: A proteomic perspective. Electrophoresis 20, 2299-2308.

Mason, A.B., T.B. Kardos and B.C. Monk. (1998) Regulation and pH-dependent expression of a bilaterally truncated yeast plasma membrane H+-ATPase. Biochim. Biophys. Acta 1372: 261-271

Seto-Young, D., B. Monk, A.B. Mason and D.S. Perlin. (1997) Exploring an antifungal target region in the plasma membrane H+-ATPase of fungi. Biochim. Biophys. Acta 1326, 249-256.

Monk, B.C., A. B. Mason, G. Abramochkin, J.E. Haber, D. Seto-Young and D.S. Perlin. (1995) The yeast plasma membrane proton pumping ATPase is a viable antifungal target. 1. Effects of the cysteine-modifying reagent omeprazole. Biochim. Biophys. Acta 1239, 81-90.

Monk, B.C. and D.S. Perlin. (1994) Plasma membrane proton pumps as promising new antifungal targets. CRC Critical Reviews in Microbiology 20, 209-233.

Email

brian.monk@stonebow.otago.ac.nz

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