Tim BEACON

Professor Diane Kelly

Professor of Microbiology and Infection

d.kelly@swansea.ac.uk

Swansea University

Areas of Expertise

  • Sterol metabolism
  • Microbial cytochromes P450 (CYPs)
  • Microbial resistance

Research Interests

A significant part of research effort has been concerned with the metabolic pathway leading to sterols and within EUROFAN (an EU programme set up within the yeast community in Europe to elucidate the function of all of yeast genes), Diane was invited to be part of the Lipid Node to determine alterations in sterol biosynthesis in gene-disrupted strains. Within the Transatlantic Yeast Gene Deletion Project involving EUROFAN II she was responsible for gene disruptions and strain verification as the UK laboratory involved in this historic project. It was the first time every gene of an organism had been specifically deleted to determine its contribution to viability and readily observable phenotype. The paper in Nature (>1900 citations) is important not only in yeast genetics, but also a paradigm of post-genomic approaches that is now integral to her own research in the area of CYPs.

CYPs are part of a superfamily of as yet unknown size, but in some microorganisms represent over 1% of the genes. Discovering their function is a major task as these are of biotechnological interest for making drugs and in their role as drug targets. Their general function is in cellular biosynthetic reactions such as in fatty acid, steroid and prostaglandin synthesis and in secondary metabolism (natural product synthesis) in plants and microbes. Human cytochromes P450 are of central importance in the metabolism of carcinogens, drugs and pesticides. Present research maintains a focus on CYPs involved in sterol metabolism, defining function for so-called “orphan” genes and studies related to antimicrobial action and antimicrobial drug resistance.

More recently Professor Kelly was invited to lead an international team (Eurofung, FP6) to identify all CYPs present in A. nidulans with the aim of defining function using a bioinformatics approach.

BEACON Activities

  • Chair Swansea Local Management Group
  • Science project design and management

Future Plans

Exploit microbial use of biomass to produce chemical entities of use to industry and pharma.

Recent Publications

Sewell TR, Hawkins NJ, Stotz HU, Huang YJ, Kelly SL, Kelly DE, Fraaije B, Fitt BDL. Azole sensitivity in Leptosphaeria pathogens of oilseed rape: the role of lanosterol 14alpha-demethylase. Scientific Reports. 2017, 7:15849.

Hull CM, Warrilow AGS, Rolley NJ, Price CL, Donnison IS, Kelly DE, Kelly SL. Co-production of 11alpha-hydroxyprogesterone and ethanol using recombinant yeast expressing fungal steroid hydroxylases. Biotechnol Biofuels. 2017, 10:226.

Warrilow AGS, Parker JE, Price CL, Garvey EP, Hoekstra WJ, Schotzinger RJ, Wiederhold NP, Nes WD, Kelly DE, Kelly SL. The tetrazole VT-1161 is a potent inhibitor of Trichophyton rubrum through its inhibition T. rubrum CYP51. Antimicrobial Agents and Chemotherapy. 2017, EPub ahead of print.

Colley T, Alanio A, Kelly SL, Sehra G, Kizawa Y, Warrilow AGS, Parker JE, Kelly DE, Kimura G, Anderson-Dring L, Nakaoki T, Sunose M, Onions S, Crepin D, Lagasse F, Crittall M, Shannon J, Cooke M, Bretagne S, King-Underwood J, Murray J, Ito K, Strong P, Rapeport G. In vitro and in vivo antifungal profile of a novel and long acting inhaled azole PC945, on Aspergillus fumigatus infection. Antimicrobial Agents and Chemotherapy. 2017, doi:10.1128/AAC.02280-16.

Warrilow AG, Price CL, Parker JE, Rolley NJ, Smyrniotis CJ, Hughes DD, Thoss V, Nes WD, Kelly DE, Holman TR, Kelly SL. Azole antifungal sensitivity of sterol 14α-demethylase (CYP51) and CYP5218 from Malassezia globosa. Scientific Reports. 2016, 6, 27690.

Warrilow AG, Parker JE, Price CL, Nes WD, Garvey EP, Hoekstra WJ, Schotzinger RJ, Kelly DE, Kelly SL. The invesitgational drug VT-1129 is a highly potent inhibitor of Cryptococcus species CYP51 but only weakly inhibits the human enzyme. Antimicrobial Agents and Chemotherapy. 2016, 60(8), 4530-4538.

Warrilow AGS, Parker JE, Price CL, Nes WD, Kelly SL, Kelly DE. CYP51-mediated azole resistance in Aspergillus fumigatus: an in vitro biochemical study. Antimicrobial Agents and Chemotherapy. 2015, 59(12), 7771-7778.

Lamb DC, Warrilow AG, Rolley NJ, Parker JE, Nes WD, Smith SN, Kelly DE, Kelly SL. Azole antifungal agents to treat the human pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through inhibition of sterol 14alpha-demethylase (CYP51). Antimicrobial Agents and Chemotherapy. 2015, 59(8), 4707-4713.

Price CL, Parker JE, Warrilow AGS, Kelly DE, Kelly SL. Azole fungicides - understanding resistance mechanisms in agricultural fungal pathogens. Pest Management Science. 2015, 71(8), 1054-1058.

Price CL, Warrilow AGS, Parker JE, Mullins JGL, Nes WD, Kelly DE, Kelly SL. Novel substrate specificity and temperature sensitive activity of Mycosphaerella graminicola CYP51 (MgCYP51) supported by the native NADPH cytochrome P450 reductase (CPR). Applied and Environmental Microbiology. 2015, 81(10), 3379-3386.

Salvage R, Hull CM, Kelly DE, Kelly SL. Use of 70% alcohol for the routine removal of microbial hard surface bioburden in life science cleanrooms. Future Microbiology. 2014, 9(10), 1123-1130.

Hull CM, Loveridge EJ, Donnison IS, Kelly DE, Kelly SL. Co-production of bioethanol and probiotic yeast biomass from agricultural feedstock: application of the rural biorefinery concept. AMB Express. 2014, 4, Epub.

Hull CM, Loveridge EJ, Rolley NJ, Donnison IS, Kelly SL, Kelly DE. Co-production of ethanol and squalene using a Saccharomyces cerevisiae ERG1 (squalene epoxidase) mutant and agro-industrial feedstock. Biotechnology for Biofuels. 2014, 7, Epub.

Warrilow AGS, Hull CM, Parker JE, Garvey EP, Hoekstra WJ, Moore WR, Schotzinger RJ, Kelly DE, Kelly SL. The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrobial Agents and Chemotherapy. 2014, Epub.

Parker JE, Warrilow AGS, Price CL, Mullins JGL, Kelly DE, Kelly SL. Resistance to antifungals that target CYP51. Journal of Chemical Biology. 2014, 7(4), 143-161. 

Warrilow AGS, Hull CM, Rolley NJ, Parker JE, Nes WD, Smith SN, Kelly DE, Kelly SL. Clotrimazole as a potent agent for treating the oomycete fish pathogen Saprolegnia parasitica through inhibition of sterol 14alpha-demethylase (CYP51). Applied and Environmental Microbiology. 2014. 80(19), 6154-6166.

Hawkins NJ, Cools HJ, Sierotzki H, Shaw MW, Knogge W, Kelly SL, Kelly DE, Fraaije BA. Paralog re-emergence: a novel, historically contingent mechanism in the evolution of antimicrobial resistance. Molecular Biology and Evolution. 2014, 31(7), 1793-1802

Hoobler EK, Rai G, Warrilow AGS, Perry SC, Smyrniotis CJ, Jadhav A, Simeonov A, Parker JE, Kelly DE, Maloney DJ, Kelly SL, Holman TR. Discovery of a novel dual fungal CYP51/human 5-lipoxygenase inhibitor: implications for anti-fungal therapy. PLoS One. 2013, 8(6), e65928.

Belic A, Pompon D, Monostory K, Kelly D, Kelly S, Rozman, D. An algorithm for rapid computational construction of metabolic networks: A cholesterol biosynthesis example. Computers in Biology and Medicine. 2013, 43(5), 471-480.

Parker JE, Warrilow AG, Cools HJ, Fraaije BA, Lucas JA, Rigdova K, Griffiths WJ, Kelly DE, KellySL. Prothioconazole and prothioconazole-desthio activity against Candida albicans sterol 14 alpha-demethylase (CaCYP51). Applied and Environmental Microbiology. 2013, 79(5), 1639-1645.

Kelly SL, Kelly DE. Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us? Philosophical Transactions of the Royal Society B 2013, 368(1612)SI, Art. No. 20120476.

Warrilow AG, Parker JE, Kelly DE, Kelly SL. Azole affinity of sterol 14 alpha-demethylase (CYP51) enzymes from Candida albicans and Homo sapiens. Antimicrobial Agents and Chemotherapy. 2013, 57(3), 1352-1360.

Newsome AW, Nelson D, Corran A, Kelly SL, Kelly DE. The cytochrome P450 complement (CYPome) of Mycosphaerella graminicola. Biotechnology and Applied Biochemistry. 2013, 60(1), 52-64.

Hull CM, Bader O, Parker JE, Weig M, Gross U, Warrilow AG, Kelly DE, Kelly SL. Two clinical isolates of Candida glabrata exhibiting reduced sensitivity to amphotericin B both harbor mutations in ERG2. Antimicrobial Agents and Chemotherapy. 2012, 56(12), 6417-6421.

Hull CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AG, Kelly DE, KellySL. Facultative sterol uptake in an ergosterol-deficient clinical isolate of Candida glabrata harboring a missense mutation in ERG11 and exhibiting cross-resistance to azoles and amphotericin B. Antimicrobial Agents and Chemotherapy. 2012, 56(8), 4223-4232.

Warrilow AGS, Mullins JGL, Hull CM, Parker JE, Lamb DC, Kelly DE, Kelly SL. S279 point mutations in Candida albicans sterol 14-alpha demethylase (CYP51) reduces in vitro inhibition by fluconazole. Antimicrobial Agents and Chemotherapy. 2012, 56(4), 2099-2107.

Cools HJ, Mullins JGL, Fraaije BA, Parker JE, Kelly DE, Lucas JA, Kelly SL. Impact of recently emerged sterol 14 alpha-demethylase (CYP51) variants of Mycosphaerella graminicola on azole fungicide sensitivity. Applied and Environmental Microbiology. 2011, 77(11), 3830-3837.

Parker JE, Warrilow AGS, Cools HJ, Martel CM, Nes, WD, Fraaije BA, Lucas JA, Kelly DE, Kelly SL. Mechanism of binding of prothioconazole to Mycosphaerella graminicola CYP51 differs from that of other azole antifungals. Applied and Environmental Microbiology. 2011, 77(4), 1460-1465.

Martel CM, Parker JE, Jackson CJ, Warrilow AGS, Rolley N, Greig C, Morris SM, Donnison IS, Kelly DE, Kelly SL. Expression of bacterial levanase in yeast enables simultaneous saccharification and fermentation of grass juice to bioethanol. Bioresource Technology. 2011, 102(2), 1503-1508.

Martel CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AGS, Rolley N, Kelly DE, Kelly SL. Identification and characterization of four azole-resistant erg3 mutants of Candida albicans. Antimicrobial Agents and Chemotherapy. 2010, 54(11), 4527-4533.

Martel CM, ParkerJE, Warrilow AGS, Rolley N, Kelly SL, Kelly, DE. Complementation of a Saccharomyces cerevisiae ERG11/CYP51 (sterol 14 alpha-demethylase) doxycycline-regulated mutant and screening of the azole sensitivity of Aspergillus fumigatus isoenzymes CYP51A and CYP51B. Antimicrobial Agents and Chemotherapy. 2010, 54(11), 4920-4923.

Warrilow AGS, Melo N, Martel CM, Parker JE, Kelly SL, Kelly DE. Expression, purification, and characterization of Aspergillus fumigatus sterol 14-alpha demethylase (CYP51) isoenzymes A and B. Antimicrobial Agents and Chemotherapy. 2010, 54(10), 4225-4234.

Warrilow AGS, Martel CM, Parker JE, Melo N, Lamb DC, Nes D, Kelly DE, Kelly SL. Azole binding properties of Candida albicans sterol 14-alpha demethylase (CaCYP51). Antimicrobial Agents and Chemotherapy. 2010, 54(10), 4235-4245.

Martel CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AGS, Kelly DE, Kelly SL. A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14 alpha-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B. Antimicrobial Agents and Chemotherapy. 2010, 54(9), 3578-3583.

Cools HJ, Parker JE, Kelly DE, Lucas JA, Fraaije BA, Kelly SL. Heterologous expression of mutated eburicol 14 alpha-demethylase (CYP51) proteins of Mycosphaerella graminicola to assess effects on azole fungicide Sensitivity and intrinsic protein function. Applied and Environmental Microbiology. 2010, 76(9), 2866-2872.

Martel CM, Warrilow AGS, Jackson CJ, Mullins JGL, Togawa RC, Parker JE, Morris MS, Donnison IS, Kelly DE, Kelly SL. Expression, purification and use of the soluble domain of Lactobacillus paracasei beta-fructosidase to optimise production of bioethanol from grass fructans. Bioresource Technology. 2010, 101(12), 4395- 4402.