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

Volumn 58, Issue 12, 2014, Pages 7121-7127

  Warrilow, A G S ^a   Hull, C M ^a   Parker, J E ^a   Garvey, E P ^b   Hoekstra, W J ^b   Moore, W R ^b   Schotzinger, R J ^b   Kelly, D E ^a   Kellya, S L ^a  

^a SWANSEA UNIVERSITY   (United Kingdom)

^b Viamet Pharmaceuticals   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIFUNGAL AGENT; CLOTRIMAZOLE; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; ERGOSTEROL; FLUCONAZOLE; ITRACONAZOLE; PYRROLE; PYRROLE DERIVATIVE; STEROL; STEROL 14ALPHA DEMETHYLASE; UNCLASSIFIED DRUG; VORICONAZOLE; VT 1161; CYP2C19 PROTEIN, HUMAN; CYP2C9 PROTEIN, HUMAN; CYP3A4 PROTEIN, HUMAN; CYTOCHROME P450 3A; FUNGAL PROTEIN; PROTEIN BINDING; PYRIDINE DERIVATIVE; RECOMBINANT PROTEIN; STEROL 14ALPHA DEMETHYLASE INHIBITOR; TETRAZOLE DERIVATIVE; VT-1161;

ARTICLE; ASSAY; BINDING AFFINITY; CANDIDA ALBICANS; CANDIDIASIS; CONTROLLED STUDY; DISSOCIATION CONSTANT; DRUG POTENCY; DRUG SELECTIVITY; HUMAN; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; ANTAGONISTS AND INHIBITORS; BINDING SITE; CHEMISTRY; ENZYME ASSAY; ENZYMOLOGY; ESCHERICHIA COLI; GENE EXPRESSION; GENETICS; METABOLISM; SPECIES DIFFERENCE; SYNTHESIS;

14-ALPHA DEMETHYLASE INHIBITORS; ANTIFUNGAL AGENTS; BINDING SITES; CANDIDA ALBICANS; CYTOCHROME P-450 CYP2C19; CYTOCHROME P-450 CYP2C9; CYTOCHROME P-450 CYP3A; ENZYME ASSAYS; ESCHERICHIA COLI; FUNGAL PROTEINS; GENE EXPRESSION; HUMANS; PROTEIN BINDING; PYRIDINES; RECOMBINANT PROTEINS; SPECIES SPECIFICITY; STEROL 14-DEMETHYLASE; TETRAZOLES; VORICONAZOLE;

EID: 84912083880     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.03707-14     Document Type: Article

References (39)

1. Nivoix Y, Leveque D, Herbrecht R, Koffel J-C, Beretz L, Ubeaud-Sequier G. 2008. The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin. Pharmacokinet. 47:779-792. http://dx .doi.org/10.2165/0003088-200847120-00003.
2. Shafaati M, Mast N, Beck O, Nayef R, Heo GY, Bjorkhem-Bergman L, Lutjohann D, Bjorkhem I, Pkuleva IA. 2010. The antifungal drug voriconazole is an efficient inhibitor of brain cholesterol 24S-hydroxylase in vitro and in vivo. J. Lipid Res. 51:318-323. http://dx.doi.org/10.1194/jlr .M900174-JLR200.
3. Kragie L, Turner SD, Patten CJ, Crespi CL, Stresser DM. 2002. Assessing pregnancy risks of azole antifungals using a high throughput aromatase inhibition assay. Endocr. Res. 28:129-140. http://dx.doi.org/10.1081 /ERC-120015045.
4. Wang J-L, Chang C-H, Young-Xu Y, Chan KA. 2010. Systematic review and meta-analysis of the tolerability and heptotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection. Antimicrob. Agents Chemother. 54:2409-2419. http://dx.doi.org/10.1128/AAC.01657-09.
5. Venkateswarlu K, Denning DW, Manning NJ, Kelly SL. 1996. Reduced accumulation of drug in Candida krusei accounts for itraconazole resistance. Antimicrob. Agents Chemother. 40:2443-2446.
6. Eddouzi J, Parker JE, Vale-Silva LA, Coste A, Ischer F, Kelly S, Manai M, Sanglard D. 2013. Molecular mechanisms of drug resistance in clinical Candida species isolated from Tunisian hospitals. Antimicrob. Agents Chemother. 57:3182-3193. http://dx.doi.org/10.1128/AAC.00555-13.
7. Hull CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AG, Kelly DE, Kelly SL. 2012. 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. Antimicrob. Agents Chemother. 56:4223-4232. http://dx.doi.org/10.1128 /AAC.06253-11.
8. Pfaller MA, Diekema DJ. 2007. Epidemiology of invasive candidiasis: a persistent public health problem. Clin. Microbiol. Rev. 20:133-163. http: //dx.doi.org/10.1128/CMR.00029-06.
9. Richardson MD. 2005. Changing patterns and trends in systemic fungal infections. J. Antimicrob. Chemother. 56(Suppl S1)):i5-i11. http://dx.doi .org/10.1093/jac/dki218.
10. Sims CR, Ostrosky-Zeichner L, Rex JH. 2005. Invasive candidiasis in immunocompromised hospitalized patients. Arch. Med. Res. 36:660-671. http://dx.doi.org/10.1016/j.arcmed.2005.05.015.
11. Coste A, Selmecki A, Forche A, Diogo D, Bougnoux ME, d'Enfert C, Berman J, Sanglard D. 2007. Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates. Eukaryot. Cell 6:1889-1904. http://dx.doi.org/10.1128/EC.00151-07.
12. Morio F, Loge C, Besse B, Hennequin C, Le Pape P. 2010. Screening for amino acid substitutions in the Candida albicans Erg11 protein of azolesusceptible and azole-resistant clinical isolates: new substitutions and a review of the literature. Diagn. Microbiol. Infect. Dis. 66:373-384. http: //dx.doi.org/10.1016/j.diagmicrobio.2009.11.006.
13. Suzuki Y, Tokimatsu I, Sato Y, Kawasaki K, Sato Y, Goto T, Hashinaga K, Itoh H, Hiramatsu K, Kadota J. 2013. Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity. Clin. Chim. Acta 424:119-122. http://dx.doi.org/10.1016/j.cca .2013.05.025.
14. Hoekstra WJ, Garvey EP, Moore WR, Rafferty SW, Yates CM, Schotzinger RJ. 2014. Design and optimization of highly-selective fungal CYP51 inhibitors. Bioorg. Med. Chem. Lett. 24:3455-3458. http://dx.doi.org/10 .1016/j.bmcl.2014.05.068.
15. Warrilow AGS, Parker JE, Kelly DE, Kelly SL. 2013. Azole affinity of sterol 14 -demethylase (CYP51) enzymes from Candida albicans and Homo sapiens. Antimicrob. Agents Chemother. 57:1352-1360. http://dx .doi.org/10.1128/AAC.02067-12.
16. Lepesheva GI, Park HW, Hargrove TY, Vanhollebeke B, Wawrzak Z, Harp JM, Sundaramoorthy M, Nes WD, Pays E, Chaudhuri M, Villalta F, Waterman MR. 2010. Crystal structures of Trypanosoma brucei sterol 14 -demethylase and implications for selective treatment of human infections. J. Biol. Chem. 285:1773-1780. http://dx.doi.org/10.1074/jbc .M109.067470.
17. von Wachenfeldt C, Richardson TH, Cosme J, Johnson EF. 1997. Microsomal P450 2C3 is expressed as a soluble dimer in Escherichia coli following modifications of its N-terminus. Arch. Biochem. Biophys. 339: 107-114. http://dx.doi.org/10.1006/abbi.1996.9859.
18. Barnes HJ, Arlotto MP, Waterman MR. 1991. Expression and enzymatic activity of recombinant cytochrome P450 17 -hydroxylase in Escherichia coli. Proc. Natl. Acad. Sci. U. S. A. 88:5597-5601. http://dx.doi.org/10 .1073/pnas.88.13.5597.
19. Lamb DC, Kelly DE, Waterman MR, Stromstedt M, Rozman D, Kelly SL. 1999. Characteristics of the heterologously expressed human lanosterol 14 -demethylase (other names: P45014DM, CYP51, P45051) and inhibition of the purified human and Candida albicans CYP51 with azole antifungal agents. Yeast 15:755-763. http://dx.doi.org/10.1002/(SICI)1097 -0061(19990630)15:9-755::AID-YEA417-3.0.CO;2-8.
20. Lutz JD, Dixit V, Yeung CK, Dickmann LJ, Zelter A, Thatcher JA, Nelson WL, Isoherranen N. 2009. Expression and functional characterization of cytochrome P450 26A1, a retinoic acid hydroxylase. Biochem. Pharmacol. 77:258-268. http://dx.doi.org/10.1016/j.bcp.2008.10.012.
21. Morrison JF. 1969. Kinetics of the reversible inhibition of enzymecatalysed reactions by tight-binding inhibitors. Biochim. Biophys. Acta 185:269-286. http://dx.doi.org/10.1016/0005-2744(69)90420-3.
22. Venkateswarlu K, Lamb DC, Kelly DE, Manning NJ, Kelly SL. 1998. The N-terminal membrane domain of yeast NADPH-cytochrome P450 (CYP) oxidoreductase is not required for catalytic activity in sterol biosynthesis or in reconstitution of CYP activity. J. Biol. Chem. 273:4492-4496. http: //dx.doi.org/10.1074/jbc.273.8.4492.
23. Venkateswarlu K, Denning DW, Manning NJ, Kelly SL. 1995. Resistance to fluconazole in Candida albicans from AIDS patients correlated with reduced intracellular accumulation of drug. FEMS Microbiol. Lett. 131: 337-341. http://dx.doi.org/10.1111/j.1574-6968.1995.tb07797.x.
24. Clinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard M27-A3, 3rd ed. Clinical and Laboratory Standards Institute, Wayne, PA.
25. Parker JE, Merkamm M, Manning NJ, Pompon D, Kelly SL, Kelly DE. 2008. Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homologous locus. Antimicrob. Agents Chemother. 52:3597-3603. http: //dx.doi.org/10.1128/AAC.00517-08.
26. Cheng S, Clancy CJ, Nguyen KT, Clapp W, Nguyen H. 2007. A Candida albicans petite mutant strain with uncoupled oxidative phosphorylation overexpressesMDR1and has diminished susceptibility to fluconazole and voriconazole. Antimicrob. Agents Chemother. 51:1855-1858. http://dx .doi.org/10.1128/AAC.00182-07.
27. Martel CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AGS, Kelly DE, Kelly SL. 2010.Aclinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14 -demethylase) and ERG5 (encoding C22-desaturase) is cross-resistant to azoles and amphotericin B. Antimicrob. Agents Chemother. 54:3578-3583. http://dx.doi.org/10.1128/AAC.00303-10.
28. Jefcoate CR, Gaylor JL, Calabrese RL. 1969. Ligand interactions with cytochrome P450. I. Binding of primary amines. Biochemistry 8:3455-3463.
29. Jefcoate CR. 1978. Measurement of substrate and inhibitor binding to microsomal cytochrome P-450 by optical-difference spectroscopy. Methods Enzymol. 52:258-279. http://dx.doi.org/10.1016/S0076-6879(78)52029-6.
30. Strushkevich N, Usanov SA, Park H-W. 2010. Structural basis of human CYP51 inhibition by antifungal azoles. J. Mol. Biol. 397:1067-1078. http: //dx.doi.org/10.1016/j.jmb.2010.01.075.
31. Locuson CW, Hutzler JM, Tracy TS. 2007. Visible spectra of type II cytochrome P450-drug complexes: evidence that "incomplete" heme coordination is common. Drug Metab. Dispos. 35:614-622. http://dx.doi .org/10.1124/dmd.106.012609.
32. Kelly SL, Lamb DC, Kelly DE, Loeffler J, Einsele H. 1996. Resistance to fluconazole and amphotericin B in Candida albicans from AIDS patients. Lancet 348:1523-1524.
33. Watson PF, Rose ME, Ellis SW, England H, Kelly SL. 1989. Defective sterol C5-6 desaturation and azole resistance: a new hypothesis for the mode of action of azole antifungals. Biochem. Biophys. Res. Commun. 164:1170-1175. http://dx.doi.org/10.1016/0006-291X(89)91792-0.
34. Zhang W, Ramamoorthy Y, Kilicarslan T, Nolte H, Tyndale RF, Sellers EM. 2002. Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab. Dispos. 30:314-318. http://dx.doi.org/10.1124/dmd .30.3.314.
35. Niwa T, Shiraga T, Takagi A. 2005. Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol. Pharm. Bull. 28:1805-1808. http://dx.doi.org/10.1248 /bpb.28.1805.
36. Zhang S, Pillai VC, Mada SR, Strom S, Venkataramanan R. 2012. Effect of voriconazole and other azole antifungal agents on CYP3A activity and metabolism of tacrolimus in human liver microsomes. Xenobiotica 42: 409-416. http://dx.doi.org/10.3109/00498254.2011.631224.
37. Gao F, Johnson DL, Ekins S, Janiszewski J, Kelly KG, Meyer RD, West M. 2002. Optimizing higher throughput methods to assess drug-drug interactions for CYP1A2, CYP2C9, CYP2C19, CYP2D6, rCYP2D6, and CYP3A4 in vitro using a single point IC(5). J. Biomol. Screen. 7:373-382. http://dx.doi.org/10.1089/108705702320351231.
38. Obach RS, Walsky RL, Venkatakrishnan K, Gaman EA, Houston JB, Tremaine LM. 2006. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J. Pharmacol. Exp. Ther. 316:336-348. http://dx.doi.org/10.1124/jpet.105.093229.
39. Humphrey MJ, Jevons S, Tarbit MH. 1985. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans. Antimicrob. Agents Chemother. 28:648-653. http://dx.doi .org/10.1128/AAC.28.5.648.