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Comparison of anti-Candida albicans activities of halogenomethylsulfonyl derivatives

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Abstract

A rapidly growing resistance of Candida spp. requires a search for bioactive compounds with fungicidal or fungistatic activity. In this context a characteristics and comparison of antifungal properties of 19 sulfone derivatives were conducted. MICs of the Compounds were determined using the M27-A3 protocol following CLSI recommendations. The SAP expression was analyzed using RT-PCR; relative quantification was normalized against ACT1 in cells grown in YEPD and on Caco-2. 79 % of sulfone derivatives (15 out of 19) exhibited an activity against Candida albicans in the tested concentrations. While the addition of both chlorine and bromine atoms to halogenomethylsulfonyl groups stimulates sulfone’s antifungal activity, a chlorine atom more effectively up-regulates antifungal properties of the tested sulfones. The insertion of a fluorine atom has a binary effect on antifungal properties of the tested sulfones. The fluorine atom enhances anti-Candida properties when introduced to the aromatic ring, while its presence in halogenomethylsulfonyl group generally lowers the Compound’s efficiency. The deletion of particular SAP genes resulted in an increased susceptibility of C. albicans toward sulfones indicating the role of this gene family in resistance mechanisms. Furthermore, RT-PCR analysis demonstrated that sulfone derivatives inhibit the SAP2 expression but not that of SAP7.

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Abbreviations

CLSI:

Clinical Laboratory Standards Institute

DMSO:

Dimethyl sulfoxide

EMEM:

Eagle’s minimum essential medium

FCS:

Fetal calf serum

MIC:

Minimal inhibitory concentration

PBS:

Phosphate-based saline

RPMI 1640:

Roswell Park Memorial Institute Medium

RT-PCR:

Reverse transcription polymerase chain reaction

SAP :

Secreted aspartic proteases

YEPD:

Yeast extract-peptone-dextrose growth medium

XTT:

Sodium 3′ -[1-(phenylaminocarbonyl)- 3,4-tetrazolium]-bis (4-methyloxy-6-nitro) benzene sulfonic acid hydrate

References

  • Amberg DC, Burke DJ, Strathern JN (2005) Yeast RNA isolations, techniques and protocols #6. In: Amberg DC, Burke DJ, Strathern JN (eds) Methods in yeast genetics, 2005th edn. Cold Spring Harbor Laboratory Press, New York, p 127

    Google Scholar 

  • Aoki W, Kitahara N, Miura N, Morisaka H, Yamamoto Y, Koruda K, Ueda M (2012) Candida albicans possesses Sap7 as a Pepstatin A—insensitive secreted aspartic protease. PLoS One 7:e32513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Balish EA (2009) URA3 null mutant of Candida albicans (CAI-4) causes oro-oesophageal and gastric candidiasis and is lethal for gnotobiotic, transgenic mice (Tgepsilon26) that are deficient in both natural killer and T cells. J Med Microbiol 58:290–295

    Article  PubMed  Google Scholar 

  • Biswas S, Van Dijck P, Datta A (2007) Environmental sensing and signal transduction pathways regulating morphopathogenic determinants of Candida albicans. Microbiol Mol Biol Rev 71:348–376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bondaryk M, Ochal Z, Staniszewska M (2014) Sulfone derivatives reduce growth, adhesion and aspartic protease SAP2 gene expression. World J Microbiol Biotechnol 30:2511–2521

    Article  CAS  PubMed  Google Scholar 

  • Borys KM, Korzyński MD, Ochal Z (2012) Derivatives of phenyl tribromomethyl sulfone as novel compounds with potential pesticidal activity. Beilstein J Org Chem 8:259–265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brand A, MacCallum DM, Brown AJ, Gow NA, Odds FC (2004) Ectopic expression of URA3 can influence the virulence phenotypes and proteome of Candida albicans but can be overcome by targeted reintegration of URA3 at the RPS10 locus. Eukaryot Cell 3:900–909

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cannon RD, Lamping E, Holmes AR, Niimi K, Tanabe K, Niimi M, Monk BC (2007) Candida albicans drug resistance—another way to cope with stress. Microbiology 153:3211–3217

    Article  CAS  PubMed  Google Scholar 

  • Cheng S, Nguyen MH, Zhang Z, Jia H, Handfield M, Clancy CJ (2003) Evaluation of the roles of four Candida albicans genes in virulence by using gene disruption strains that express URA3 from the native locus. Infect Immun 71:6101–6103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • CLSI (2008) Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard. CLSI document M27-A3, 3rd edn. Clinical and Laboratory Standards Institute, Wayne

    Google Scholar 

  • Copping VM, Barelle CJ, Hube B, Gow NA (2005) Exposure of Candida albicans to antifungal agents affects expression of SAP2 and SAP9 secreted proteinase genes. J Antimicrob Chemother 55:645–654

    Article  CAS  PubMed  Google Scholar 

  • Costa CR, Jesuíno RS, Lemos JD, Fernandes OD, Souza LK, Passos XS, Silva MD (2010) Effects of antifungal agents in Sap activity of Candida albicans isolates. Mycopathologia 169:91–98

    Article  PubMed  Google Scholar 

  • Dos Santos AL (2010) HIV aspartyl protease inhibitors as promising compounds against Candida albicans. World J Biol Chem 26:21–30

    Article  Google Scholar 

  • Eggimann P, Bille J, Marchetti O (2011) Diagnosis of invasive candidiasis in the ICU. Ann Intensive Care 1:37

    Article  PubMed Central  PubMed  Google Scholar 

  • Ellepola AN, Joseph BK, Chandy R, Khan ZU (2014) The postantifungal effect of nystatin and its impact on adhesion attributes of oral Candida dubliniensis isolates. Mycoses 57:56–63

    Article  CAS  PubMed  Google Scholar 

  • Ene IV, Heilmann CJ, Sorgo AG, Walker LA, de Koster CG, Munro CA, Klis FM, Brown AJ (2012) Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans. Proteomics 12:3164–3179

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Forche A (2014) Large-scale chromosomal changes and associated fitness consequences in pathogenic fungi. Curr Fungal Infect Rep 8:163–170

    Article  PubMed Central  PubMed  Google Scholar 

  • García MG, O’Connor JE, García LL, Martínez SI, Herrero E, Agudo LD (2001) Isolation of a Candida albicans gene, tightly linked to URA3, coding for a putative transcription factor that suppresses a Saccharomyces cerevisiae aft1 mutation. Yeast 18:301–311

    Article  PubMed  Google Scholar 

  • Gillum AM, Tsay EY, Kirch DR (1984) Isolation of the Candida albicans gene expression for orotidine-5′-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations. Mol Gen Genet 198:179–182

    Article  CAS  PubMed  Google Scholar 

  • Hube B, Naglik J (2001) Candida albicans proteinases: resolving the mystery of a gene family. Microbiology 147:1997–2005

    CAS  PubMed  Google Scholar 

  • Hube B, Monod M, Schofield DA, Brown AJ, Gow NA (1994) Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans. Mol Microbiol 14:87–99

    Article  CAS  PubMed  Google Scholar 

  • Jackson BE, Wilhelmus KR, Hube B (2007) The role of secreted aspartyl proteinases in Candida albicans keratitis. Invest Ophthalmol Vis Sci 48:3559–3565

    Article  PubMed  Google Scholar 

  • Jandric Z, Gregori C, Klopf E, Radolf M, Schüller C (2013) Sorbic acid stress activates the Candida glabrata high osmolarity glycerol MAP kinase pathway. Front Microbiol 4:350

    Article  PubMed Central  PubMed  Google Scholar 

  • Kathwate GH, Karuppayil SM (2013) Antifungal properties of the anti-hypersensitive drug: aliskiren. Arch Oral Biol 58:1109–1115

    Article  CAS  PubMed  Google Scholar 

  • Kawasaki K, Masubuchi M, Morikami K, Sogabe S, Aoyama T, Ebiike H, Niizuma S, Hayase M, Fujii T, Sakata K, Shindoh H, Shiratori Y, Aoki Y, Ohtsuka T, Shimma N (2003) Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 3. Bioorg Med Chem Lett 13:87–91

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Sudbery P (2011) Candida albicans, a major human fungal pathogen. J Microbiol 49:171–177

    Article  PubMed  Google Scholar 

  • Korzyński MD, Borys KM, Białek J, Ochal Z (2014) A novel method for the synthesis of aryl trihalomethyl sulfones and their derivatization: the search for new sulfone fungicides. Tetrahedron Lett 55:745–748

    Article  Google Scholar 

  • Lermann U, Morschhäuser J (2008) Secreted aspartic proteases are not required for invasion of reconstituted human epithelia by Candida albicans. Microbiology 154:3281–3295

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Köhler J, Fink GR (1994) Suppression of hyphal formation in Candida albicans by mutation of a STE12 homolog. Science 266:1723–1726

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Lo HJ, Köhler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink GR (1997) Nonfilamentous C. albicans mutants are avirulent. Cell 90:939–949

    Article  CAS  PubMed  Google Scholar 

  • Naglik JR, Moyes D, Makwana J, Kanzaria P, Tsichlaki E, Weindl G, Tappuni AR, Rodgers CA, Woodman AJ, Challacombe SJ, Schaller M, Hube B (2008) Quantitative expression of the Candida albicans secreted aspartyl proteinase gene family in human oral and vaginal candidiasis. Microbiology 154:3266–3280

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Narasimhan B, Sharma D, Kumar P (2010) Benzoimidazole: a medicinally important heterocyclic moiety. Med Chem Res 21:269–283

    Article  Google Scholar 

  • Negredo A, Monteoliva L, Gil C, Pla J, Nombela C (1997) Cloning, analysis and one-step disruption of the ARG5,6 gene of Candida albicans. Microbiology 143:297–302

    Article  CAS  PubMed  Google Scholar 

  • Ness F, Prouzet-Mauleon V, Vieillemard A, Lefebvre F, Noël T, Crouzet M, Doignon F, Thoraval D (2010) The Candida albicans Rgd1 is a RhoGAP protein involved in the control of filamentous growth. Fungal Genet Biol 47:1001–1011

    Article  CAS  PubMed  Google Scholar 

  • Nobile CJ, Fox EP, Nett JE, Sorrells TR, Mitrovich QM, Hernday AD, Tuch BB, Andes DR, Johnson AD (2012) A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell 148:126–138

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ochal Z, Kamiński R (2005) Transformation of bromodichloromethyl-4-chlorophenyl sulfone into new compounds with potential pesticidal activity. Pol J Appl Chem 3:215–255

    Google Scholar 

  • Ochal Z, Staniszewska M, Bondaryk M, Borowiecki P (2014) Polish Patent PL P.408200, 13, May 2014

  • Pfaller MA, Diekema DJ (2012) Progress in antifungal susceptibility testing of Candida spp. by use of Clinical and Laboratory Standards Institute broth microdilution methods, 2010 to 2012. J Clin Microbiol 50:2846–2856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Puri S, Kumar R, Chadha S, Tati S, Conti HR, Hube B, Cullen PJ, Edgerton M (2012) Secreted aspartic protease cleavage of Candida albicans Msb2 activates Cek1 MAPK signalling affecting biofilm formation and oropharyngeal candidiasis. PLoS One 7:e46020

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Reuss O, Vik A, Kolter R, Morschhäuser J (2004) The SAT1 flipper, an optimized tool for gene disruption in Candida albicans. Gene 341:119–127

    Article  CAS  PubMed  Google Scholar 

  • Sardi JC, Scorzoni L, Bernardi T, Fusco-Almeida AM, Mendes Giannini MJ (2013) Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. J Med Microbiol 62:10–24

    Article  CAS  PubMed  Google Scholar 

  • Schild L, Heyken A, de Groot PW, Hiller E, Mock M, de Koster C, Horn U, Rupp S, Hube B (2011) Proteolytic cleavage of covalently linked cell wall proteins by Candida albicans Sap9 and Sap10. Eukaryot Cell 10:98–109

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Staib P, Lermann U, Blass-Warmuth J, Degel B, Würzner R, Monod M, Schirmeister T, Morschhäuser J (2008) Tetracycline-inducible expression of individual secreted aspartic proteases in Candida albicans allows isoenzyme-specific inhibitor screening. Antimicrob Agents Chemother 52:146–156

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Staniszewska M, Bondaryk M, Malewski T, Kurzątkowski W (2014a) Quantitative expression of Candida albicans aspartyl proteinase genes SAP7, SAP8, SAP9, SAP10 in human serum in vitro. Pol J Microbiol 63:15–20

    Article  CAS  PubMed  Google Scholar 

  • Staniszewska M, Bondaryk M, Zielińska P, Urbańczyk-Lipkowska Z (2014b) The in vitro effects of new D186 dendrimer on virulence factors of Candida albicans. J Antibiot 67:425–432

    Article  CAS  PubMed  Google Scholar 

  • Taylor BN, Hannemann H, Sehnal M, Biesemeier A, Schweizer A, Röllinghoff M, Schröppel K (2005) Induction of SAP7 correlated with virulence in an intravenous infection model of candidiasis but not in a vaginal infection model in mice. Infect Immun 73:7061–7063

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tsai PW, Chen YT, Hsu PC, Lan CY (2013) Study of Candida albicans and its interactions with the host: a mini review. Biomedicine 3:51–64

    Article  Google Scholar 

  • Watamoto T, Samaranayake LP, Egusa H, Yatani H, Samaranayake YH, Seneviratne CJ (2010) Susceptibility of Candida albicans filamentation-defective mutants to clinical biocides. J Hosp Infect 74:189–191

    Article  CAS  PubMed  Google Scholar 

  • Williams DW, Jordan RP, Wei XQ, Alves CT, Wise MP, Wilson MJ, Lewis MA (2013) Interactions of Candida albicans with host epithelial surfaces. J Oral Microbiol 5:22434

    Article  Google Scholar 

  • Wilson RB, Davis D, Mitchell AP (1999) Rapid hypothesis testing with Candida albicans through gene disruption with short homology regions. J Bacteriol 181:1868–1874

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wu T, Wright K, Hurst SF, Morrison CJ (2000) Enhanced extracellular production of aspartyl proteinase, a virulence factor, by Candida albicans isolates following growth in subinhibitory concentrations of fluconazole. Antimicrob Agents Chemother 44:1200–1208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xu W, He J, He M, Han F, Chen X, Pan Z, Wang J, Tong M (2011) Synthesis and antifungal activity of novel sulfone derivatives containing 1,3,4-Oxadiazole moieties. Molecules 16:9129–9141

    Article  CAS  PubMed  Google Scholar 

  • Xu QR, Yan L, Lv QZ, Zhou M, Sui X, Cao YB, Jiang YY (2014) Molecular genetic techniques for gene manipulation in Candida albicans. Virulence 5:507–520

    Article  PubMed  Google Scholar 

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Acknowledgments

The work was supported by the research project of the National Science Centre, Project DEC-2011/03/D/NZ7/06198. We are extremely grateful to many colleagues and all the individuals who were generous with their advice, and provided us with strains and reagents; Professor Hsiu-Jung Lo from National Health Research Institute in Zhunan (Taiwan) with the following strains: Can16, YLO323, HLC52, HLC54, HLC74, and HLC84; Professor Joachim Morschhäuser from University of Würzburg (Germany) with following strains: SAP1MS4B, SAP2MS4B, SAP12MS4B, SAP13MS4B, SAP23MS4C, SAP3MS4B, SAP4MS4B, SAP5MS4B, SAP6MS4B, and SAP456MS4B.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Independent Laboratory of Streptomyces and Fungi Imperfecti, National Institute of Public Health-National Institute of Hygiene, Chocimska 24, 00-791, Warsaw, Poland

    Małgorzata Bondaryk & Monika Staniszewska

  2. Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664, Warsaw, Poland

    Zbigniew Ochal

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  1. Małgorzata Bondaryk
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  2. Zbigniew Ochal
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  3. Monika Staniszewska
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Correspondence to Monika Staniszewska.

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Bondaryk, M., Ochal, Z. & Staniszewska, M. Comparison of anti-Candida albicans activities of halogenomethylsulfonyl derivatives. Med Chem Res 24, 1799–1813 (2015). https://doi.org/10.1007/s00044-014-1258-8

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