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
Similar content being viewed by others
References
Bongomin F, Gago S, Oladele RO, Denning DW (2017) J Fungi 3:57
Monk BC, Goffeau A (2008) Science 321:367
Lupetti A, Danesi R, Campa M, Del Tacca M, Kelly S (2002) Trends Mol Med 8:76–81
Cowen LE, Sanglard D, Howard SJ, Rogers PD, Perlin DS (2015) Cold Spring Harb Perspect Med 5:a019752
Revie NM, Iyer KR, Robbins N, Cowen LE (2018) Curr Opin Microbiol 45:70–76
Roemer T, Krysan DJ (2014) Cold Spring Harb Perspect Med 4:a019703
Kim K, Zilbermintz L, Martchenko M (2015) Ann Clin Microbiol Antimicrob 14:32
Cui J, Ren B, Tong Y, Dai H, Zhang L (2015) Virulence 6:362–371
Krysan DJ (2015) Fungal Genet Biol 78:93–98
Bisson WH (2012) Curr Top Med Chem 12:1883–1888
Motahari K, Badali H, Hashemi SM, Fakhim H, Mirzaei H, Vaezi A, Shokrzadeh M, Emami S (2018) Future Med Chem 10:987–1002
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
Pore VS, Agalave SG, Singh P, Shukla PK, Kumar V, Siddiqi MI (2015) Org Biomol Chem 13:6551–6561
Pore VS, Aher NG, Kumar M, Shukla PK (2006) Tetrahedron 62:11178–11186
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
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
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
Thamban-Chandrika N, Shrestha SK, Ngo HX, Howard KC, Garneau-Tsodikova S (2018) Biorg Med Chem 26:573–580
Wang Y, Xu K, Bai G, Huang L, Wu Q, Pan W, Yu S (2014) Molecules 19:11333–11340
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
Yu S, Wang L, Wang Y, Song Y, Cao Y, Jiang Y, Sun Q, Wu Q (2013) RSC Adv 3:13486–13490
Karaoun N, Renfrew AK (2015) Chem Commun 51:14038–14041
Navarro M, Cisneros-Fajardo EJ, Lehmann T, Sánchez-Delgado RA, Atencio R, Silva P, Lira R, Urbina JA (2001) Inorg Chem 40:6879–6884
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
Simpson PV, Nagel C, Bruhn H, Schatzschneider U (2015) Organometallics 34:3809–3815
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
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
Kljun J, Scott AJ, Lanišnik-Rižner T, Keiser J, Turel I (2014) Organometallics 33:1594–1601
Ząbek A, Nagaj J, Grabowiecka A, Dworniczek E, Nawrot U, Młynarz P, Jeżowska-Bojczuk M (2015) Med Chem Res 24:2005–2010
Hunsaker EW, Franz KJ (2019) Dalton Trans 48:9654–9662
Paterson BM, Donnelly PS (2011) Chem Soc Rev 40:3005–3018
Helsel ME, White EJ, Razvi SZ, Alies B, Franz KJ (2017) Metallomics 9:69–81
Festa RA, Helsel ME, Franz KJ, Thiele DJ (2014) Chem Biol 21:977–987
Mandal PK, McMurray JS (2007) J Org Chem 72:6599–6601
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
Hunsaker EW, Franz KJ (2019) Metallomics 11:2020–2032
Robbins N, Caplan T, Cowen LE (2017) Annu Rev Microbiol 71:753–775
BDBiosciences (2006) Bd bionutrients technical manual: Advanced bioprocessing. https://www.bdbiosciences.com/documents/bionutrients_tech_manual.pdf. Accessed 1 Feb 2020
Thompsett AR, Abdelraheim SR, Daniels M, Brown DR (2005) J Biol Chem 280:42750–42758
Xiao Z, Wedd AG (2010) Nat Prod Rep 27:768–789
Jones CE, Abdelraheim SR, Brown DR, Viles JH (2004) J Biol Chem 279:32018–32027
Sarkar B, Wigfield Y (1967) J Biol Chem 242:5572–5577
Yang L, McRae R, Henary MM, Patel R, Lai B, Vogt S, Fahrni CJ (2005) Proc Natl Acad Sci USA 102:11179
Ackerman CM, Lee S, Chang CJ (2017) Anal Chem 89:22–41
Xiao Z, Gottschlich L, van der Meulen R, Udagedara SR, Wedd AG (2013) Metallomics 5:501–513
Alies B, Badei B, Faller P, Hureau C (2012) Chem Eur J 18:1161–1167
Xiao Z, Brose J, Schimo S, Ackland SM, La Fontaine S, Wedd AG (2011) J Biol Chem 286:11047–11055
Xiao Z, Donnelly PS, Zimmermann M, Wedd AG (2008) Inorg Chem 47:4338–4347
(2015) Cold Spring Harb Protoc, doi 10.1101/pdb.rec085639
Hunsaker EW, Franz KJ (2019) Metallomics 11:2020–2032
Holmes-Hampton GP, Jhurry ND, McCormick SP, Lindahl PA (2013) Biochemistry 52:105–114
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
Pore VS, Jagtap MA, Agalave SG, Pandey AK, Siddiqi MI, Kumar V, Shukla PK (2012) MedChemComm 3:484–488
Helsel ME, Franz KJ (2015) Dalton Trans 44:8760–8770
Parker JE, Warrilow AGS, Price CL, Mullins JGL, Kelly DE, Kelly SL (2014) J Chem Biol 7:143–161
Hagen WR (2009) Metallomics 1:384–391
Noble SM, Johnson AD (2005) Eukaryot Cell 4:298–309
McCluskey K, Wiest A, Plamann M (2010) J Biosci 35:119–126
Klis FM, de Koster CG, Brul S (2014) Eukaryot Cell 13:2–9
Upadhayaya RS, Jain S, Sinha N, Kishore N, Chandra R, Arora SK (2004) Eur J Med Chem 39:579–592
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
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
González-Cabrera D, Koivisto BD, Leigh DA (2007) Chem Commun 4218–4220
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
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
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
Corresponding author
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.
Rights and permissions
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-020-01796-x