Skip to main content

Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans

JBIC Journal of Biological Inorganic Chemistry volume 25, pages 729–745 (2020)Cite this article

Abstract

Abstract

Azole antifungals are an important class of antifungal drugs due to their low cost, ability to be administered orally, and broad-spectrum activity. However, their widespread and long-term use have given rise to adaptation mechanisms that render these compounds less effective against common fungal pathogens, including Candida albicans. New antifungals are desperately needed as drug-resistant strains become more prevalent. We recently showed that copper supplementation potentiates the activity of the azole antifungal fluconazole against the opportunistic fungal pathogen C. albicans. Here, we report eight new azole analogues derived from fluconazole in which one triazole group has been replaced with a metal-binding group, a strategy designed to enhance potentiation of azole antifungal activity by copper. The bioactivity of all eight compounds was tested and compared to that of fluconazole. Three of the analogues showed activity against C. albicans and two had lower levels of trailing growth. One compound, Flu-TSCZ, was found to impact the levels, speciation, and bioavailability of cellular metals.

Graphic abstract

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Scheme 1.
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. Bongomin F, Gago S, Oladele RO, Denning DW (2017) J Fungi 3:57

    Google Scholar 

  2. Monk BC, Goffeau A (2008) Science 321:367

    CAS  PubMed  Google Scholar 

  3. Lupetti A, Danesi R, Campa M, Del Tacca M, Kelly S (2002) Trends Mol Med 8:76–81

    CAS  PubMed  Google Scholar 

  4. Cowen LE, Sanglard D, Howard SJ, Rogers PD, Perlin DS (2015) Cold Spring Harb Perspect Med 5:a019752

    PubMed Central  Google Scholar 

  5. Revie NM, Iyer KR, Robbins N, Cowen LE (2018) Curr Opin Microbiol 45:70–76

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Roemer T, Krysan DJ (2014) Cold Spring Harb Perspect Med 4:a019703

    PubMed  PubMed Central  Google Scholar 

  7. Kim K, Zilbermintz L, Martchenko M (2015) Ann Clin Microbiol Antimicrob 14:32

    PubMed  PubMed Central  Google Scholar 

  8. Cui J, Ren B, Tong Y, Dai H, Zhang L (2015) Virulence 6:362–371

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Krysan DJ (2015) Fungal Genet Biol 78:93–98

    CAS  PubMed  Google Scholar 

  10. Bisson WH (2012) Curr Top Med Chem 12:1883–1888

    CAS  PubMed  Google Scholar 

  11. Motahari K, Badali H, Hashemi SM, Fakhim H, Mirzaei H, Vaezi A, Shokrzadeh M, Emami S (2018) Future Med Chem 10:987–1002

    CAS  PubMed  Google Scholar 

  12. Liao J, Yang F, Zhang L, Chai X, Zhao Q, Yu S, Zou Y, Meng Q, Wu Q (2015) Arch Pharmacal Res 38:470–479

    CAS  Google Scholar 

  13. Pore VS, Agalave SG, Singh P, Shukla PK, Kumar V, Siddiqi MI (2015) Org Biomol Chem 13:6551–6561

    CAS  PubMed  Google Scholar 

  14. Pore VS, Aher NG, Kumar M, Shukla PK (2006) Tetrahedron 62:11178–11186

    CAS  Google Scholar 

  15. He X, Jiang Y, Zhang Y, Wu S, Dong G, Liu N, Liu Y, Yao J, Miao Z, Wang Y, Zhang W, Sheng C (2015) MedChemComm 6:653–664

    CAS  Google Scholar 

  16. Zambrano-Huerta A, Cifuentes-Castañeda DD, Bautista-Renedo J, Mendieta-Zerón H, Melgar-Fernández RC, Pavón-Romero S, Morales-Rodríguez M, Frontana-Uribe BA, González-Rivas N, Cuevas-Yañez E (2019) Med Chem Res 28:571–579

    CAS  Google Scholar 

  17. Ptaszyńska N, Olkiewicz K, Okońska J, Gucwa K, Łęgowska A, Gitlin-Domagalska A, Dębowski D, Lica J, Heldt M, Milewski S, Ng TB, Rolka K (2019) Peptides 117:170079

    PubMed  Google Scholar 

  18. Thamban-Chandrika N, Shrestha SK, Ngo HX, Howard KC, Garneau-Tsodikova S (2018) Biorg Med Chem 26:573–580

    CAS  Google Scholar 

  19. Wang Y, Xu K, Bai G, Huang L, Wu Q, Pan W, Yu S (2014) Molecules 19:11333–11340

    PubMed  PubMed Central  Google Scholar 

  20. Zou Y, Yu S, Li R, Zhao Q, Li X, Wu M, Huang T, Chai X, Hu H, Wu Q (2014) Eur J Med Chem 74:366–374

    CAS  PubMed  Google Scholar 

  21. Yu S, Wang L, Wang Y, Song Y, Cao Y, Jiang Y, Sun Q, Wu Q (2013) RSC Adv 3:13486–13490

    CAS  Google Scholar 

  22. Karaoun N, Renfrew AK (2015) Chem Commun 51:14038–14041

    CAS  Google Scholar 

  23. Navarro M, Cisneros-Fajardo EJ, Lehmann T, Sánchez-Delgado RA, Atencio R, Silva P, Lira R, Urbina JA (2001) Inorg Chem 40:6879–6884

    CAS  PubMed  Google Scholar 

  24. Iniguez E, Sanchez A, Vasquez MA, Martinez A, Olivas J, Sattler A, Sanchez-Delgado RA, Maldonado RA (2013) J Biol Inorg Chem 18:779–790

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Simpson PV, Nagel C, Bruhn H, Schatzschneider U (2015) Organometallics 34:3809–3815

    CAS  Google Scholar 

  26. Betanzos-Lara S, Chmel NP, Zimmerman MT, Barron-Sosa LR, Garino C, Salassa L, Rodger A, Brumaghim JL, Gracia-Mora I, Barba-Behrens N (2015) Dalton Trans 44:3673–3685

    CAS  PubMed  Google Scholar 

  27. Betanzos-Lara S, Gomez-Ruiz C, Barron-Sosa LR, Gracia-Mora I, Flores-Alamo M, Barba-Behrens N (2012) J Inorg Biochem 114:82–93

    CAS  PubMed  Google Scholar 

  28. Kljun J, Scott AJ, Lanišnik-Rižner T, Keiser J, Turel I (2014) Organometallics 33:1594–1601

    CAS  Google Scholar 

  29. Ząbek A, Nagaj J, Grabowiecka A, Dworniczek E, Nawrot U, Młynarz P, Jeżowska-Bojczuk M (2015) Med Chem Res 24:2005–2010

    PubMed  Google Scholar 

  30. Hunsaker EW, Franz KJ (2019) Dalton Trans 48:9654–9662

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Paterson BM, Donnelly PS (2011) Chem Soc Rev 40:3005–3018

    CAS  PubMed  Google Scholar 

  32. Helsel ME, White EJ, Razvi SZ, Alies B, Franz KJ (2017) Metallomics 9:69–81

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Festa RA, Helsel ME, Franz KJ, Thiele DJ (2014) Chem Biol 21:977–987

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mandal PK, McMurray JS (2007) J Org Chem 72:6599–6601

    CAS  PubMed  Google Scholar 

  35. Rosenberg A, Ene IV, Bibi M, Zakin S, Segal ES, Ziv N, Dahan AM, Colombo AL, Bennett RJ, Berman J (2018) Nat Commun 9:2470

    PubMed  PubMed Central  Google Scholar 

  36. Hunsaker EW, Franz KJ (2019) Metallomics 11:2020–2032

    CAS  PubMed  Google Scholar 

  37. Robbins N, Caplan T, Cowen LE (2017) Annu Rev Microbiol 71:753–775

    CAS  PubMed  Google Scholar 

  38. BDBiosciences (2006) Bd bionutrients technical manual: Advanced bioprocessing. https://www.bdbiosciences.com/documents/bionutrients_tech_manual.pdf. Accessed 1 Feb 2020

  39. Thompsett AR, Abdelraheim SR, Daniels M, Brown DR (2005) J Biol Chem 280:42750–42758

    CAS  PubMed  Google Scholar 

  40. Xiao Z, Wedd AG (2010) Nat Prod Rep 27:768–789

    CAS  PubMed  Google Scholar 

  41. Jones CE, Abdelraheim SR, Brown DR, Viles JH (2004) J Biol Chem 279:32018–32027

    CAS  PubMed  Google Scholar 

  42. Sarkar B, Wigfield Y (1967) J Biol Chem 242:5572–5577

    CAS  PubMed  Google Scholar 

  43. Yang L, McRae R, Henary MM, Patel R, Lai B, Vogt S, Fahrni CJ (2005) Proc Natl Acad Sci USA 102:11179

    CAS  PubMed  Google Scholar 

  44. Ackerman CM, Lee S, Chang CJ (2017) Anal Chem 89:22–41

    CAS  PubMed  Google Scholar 

  45. Xiao Z, Gottschlich L, van der Meulen R, Udagedara SR, Wedd AG (2013) Metallomics 5:501–513

    CAS  PubMed  Google Scholar 

  46. Alies B, Badei B, Faller P, Hureau C (2012) Chem Eur J 18:1161–1167

    CAS  PubMed  Google Scholar 

  47. Xiao Z, Brose J, Schimo S, Ackland SM, La Fontaine S, Wedd AG (2011) J Biol Chem 286:11047–11055

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Xiao Z, Donnelly PS, Zimmermann M, Wedd AG (2008) Inorg Chem 47:4338–4347

    CAS  PubMed  Google Scholar 

  49. (2015) Cold Spring Harb Protoc, doi 10.1101/pdb.rec085639

  50. Hunsaker EW, Franz KJ (2019) Metallomics 11:2020–2032

    CAS  PubMed  Google Scholar 

  51. Holmes-Hampton GP, Jhurry ND, McCormick SP, Lindahl PA (2013) Biochemistry 52:105–114

    CAS  PubMed  Google Scholar 

  52. Papadopoulou MV, Bloomer WD, Lepesheva GI, Rosenzweig HS, Kaiser M, Aguilera-Venegas B, Wilkinson SR, Chatelain E, Ioset J-R (2015) J Med Chem 58:1307–1319

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Pore VS, Jagtap MA, Agalave SG, Pandey AK, Siddiqi MI, Kumar V, Shukla PK (2012) MedChemComm 3:484–488

    CAS  Google Scholar 

  54. Helsel ME, Franz KJ (2015) Dalton Trans 44:8760–8770

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Parker JE, Warrilow AGS, Price CL, Mullins JGL, Kelly DE, Kelly SL (2014) J Chem Biol 7:143–161

    PubMed  PubMed Central  Google Scholar 

  56. Hagen WR (2009) Metallomics 1:384–391

    CAS  PubMed  Google Scholar 

  57. Noble SM, Johnson AD (2005) Eukaryot Cell 4:298–309

    CAS  PubMed  PubMed Central  Google Scholar 

  58. McCluskey K, Wiest A, Plamann M (2010) J Biosci 35:119–126

    CAS  PubMed  Google Scholar 

  59. Klis FM, de Koster CG, Brul S (2014) Eukaryot Cell 13:2–9

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Upadhayaya RS, Jain S, Sinha N, Kishore N, Chandra R, Arora SK (2004) Eur J Med Chem 39:579–592

    CAS  PubMed  Google Scholar 

  61. Y. J. Song, Z. J.; Pandey, A.; Scarborough, R. M.; Scarborough, C. Factor XA Inhibitors.” Pub. No.: US 2007/0259924 A1. Appl. No.: 11/744,735. Filed: May 4, 2007

  62. Wu C-F, Zhao X, Lan W-X, Cao C, Liu J-T, Jiang X-K, Li Z-T (2012) J Org Chem 77:4261–4270

    CAS  PubMed  Google Scholar 

  63. González-Cabrera D, Koivisto BD, Leigh DA (2007) Chem Commun 4218–4220

  64. Kulandaivelu U, Shireesha B, Mahesh C, Vidyasagar JV, Rao TR, Jayaveera KN, Saiko P, Graser G, Szekeres T, Jayaprakash V (2013) Med Chem Res 22:2802–2808

    CAS  Google Scholar 

  65. Liu K, Lu H, Hou L, Qi Z, Teixeira C, Barbault F, Fan BT, Liu S, Jiang S, Xie L (2008) J Med Chem 51:7843–7854

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Prof. Val Culotta (Johns Hopkins University, Baltimore, MD) for providing the two strains of C. albicans (KC2 and crp1Δ/Δ), Prof. Alistair Brown (University of Exeter, Exeter, UK) for providing the SC5314 and ctr1Δ/Δ strains of C. albicans, and Prof. Dennis Thiele (Duke University, Durham, NC) for providing the two strains of C. neoformans (WT H99 and ctr1Δ ctr4Δ). This work was supported by the National Institutes of Health (Grant GM084176). E. W. H. acknowledges support from the United States Department of Education GAANN Fellowship (Award No. P200A150114).

Author information

Authors and Affiliations

  1. Department of Chemistry, French Family Science Center, Duke University, 124 Science Drive, Durham, NC, 27708, USA

    Elizabeth W. Hunsaker, Katherine J. McAuliffe & Katherine J. Franz

Authors
  1. Elizabeth W. Hunsaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katherine J. McAuliffe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katherine J. Franz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katherine J. Franz.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 3781 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hunsaker, E.W., McAuliffe, K.J. & Franz, K.J. Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans. J Biol Inorg Chem 25, 729–745 (2020). https://doi.org/10.1007/s00775-020-01796-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-020-01796-x

Keywords

  • Antifungal
  • Azole
  • Copper
  • Metals in medicine
  • Candida albicans
  • Homeostasis