Skip to main content

Advertisement

SpringerLink
Log in

Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis

  • Original Article
  • Published:
Molecular Genetics and Genomics Aims and scope Submit manuscript

Abstract

Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), the most common systemic mycosis in Latin America. PCM treatment involves a long-term chemotherapeutic approach and relapses occur at an alarming frequency. Moreover, the emergence of strains with increased drug-resistance phenotypes puts constant pressure on the necessity to develop new alternatives to treat systemic mycoses. In this work, we show that the phenothiazine (PTZ) derivative thioridazine (TR) inhibits in vitro growth of P. brasiliensis yeasts at micromolar concentrations. We employed microarray hybridization to examine how TR affects gene expression in this fungus, identifying ~1800 genes that were modulated in response to this drug. Dataset evaluation showed that TR inhibits the expression of genes that control the onset of the cell wall integrity (CWI) response, hampering production of all major structural polysaccharides of the fungal cell wall (chitin, α-glucan and β-glucan). Although TR and other PTZs have been shown to display antimicrobial activity by various mechanisms, inhibition of CWI signaling has not yet been reported for these drugs. Thus, TR may provide a novel approach to treat fungal infections by targeting cell wall biogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Amaral L, Viveiros M (2012) Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections. Int J Antimicrob Agents 39(5):376–380

    Article  PubMed  CAS  Google Scholar 

  • Amaral L, Kristiansen J, Lorian V (1992) Synergic effect of chlorpromazine on the activity of some antibiotics. J Antimicrob Chemother. 30(4):556–558

    Article  PubMed  CAS  Google Scholar 

  • Amaral L, Kristiansen JE, Viveiros M, Atouguia J (2001) Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as antituberculosis therapy. J Antimicrob Chemother 47:505–511

    Article  PubMed  CAS  Google Scholar 

  • Blankenship JR, Fanning S, Hamaker JJ, Mitchell AP (2010) An extensive circuitry for cell wall regulation in Candida albicans. PLoS Pathog 6(2):e1000752

    Article  PubMed  PubMed Central  Google Scholar 

  • Bousquet A, Dussart C, Drouillard I, Charbel EC, Boiron P (2007) Imported mycosis: a review of paracoccidioidomycosis. Med Mal Infect. 37(3):210–214

    Article  Google Scholar 

  • Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaasterland T, Glenisson P, Holstege FC, Kim IF, Markowitz V, Matese JC, Parkinson H, Robinson A, Sarkans U, Schulze-Kremer S, Stewart J, Taylor R, Vilo J, Vingron M (2001) Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet 29:365–371

    Article  PubMed  CAS  Google Scholar 

  • Brummer E, Castaneda E, Restrepo A (1993) Paracoccidioidomycosis: an update. Clin Microbiol Rev 6(2):89–117

    PubMed  PubMed Central  CAS  Google Scholar 

  • Caetano W, Tabak M (2000) Interaction of chlorpromazine and trifluoperazine with anionic sodium dodecyl sulfate (SDS) micelles: eletronic absorption and fluorescence studies. J Colloid Interface Sci 225:69–81

    Article  PubMed  CAS  Google Scholar 

  • Camacho E, Sepulveda VE, Goldman WE, San-Blas G, Niño-Vega GA (2012) Expression of Paracoccidioides brasiliensis AMY1 in a Histoplasma capsulatum amy1 mutant, relates an α-(1,4)-amylase to cell wall α-(1,3)-glucan synthesis. PLoS One 7(11):e50201

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chamoun-Emanuelli AM, Pecheur EI, Simeon RL, Huang D, Cremer PS, Chen Z (2013) Phenothiazines inhibit hepatitis C virus entry, likely by increasing the fluidity of cholesterol-rich membranes. Antimicrob Agents Chemother 57(6):2571–2581

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen LM, Xu YH, Zhou CL, Zhao J, Li CY, Wang R (2010) Overexpression of CDR1 and CDR2 genes plays an important role in fluconazole resistance in Candida albicans with G487T and T916C mutations. J Int Med Res 38:536–545

    Article  PubMed  CAS  Google Scholar 

  • Corneliussen B, Holm M, Waltersson Y, Onions J, Hallberg B, Thornell A, Grundström T (1994) Calcium/calmodulin inhibition of basic helix-loop-helix transcription factor domains. Nature 368:760–764

    Article  PubMed  CAS  Google Scholar 

  • Crowle AJ, Douvas GS, May MH (1992) Chlorpromazine: a drug potentially useful for treating mycobacterial infections. Chemotherapy 38(6):410–419

    Article  PubMed  CAS  Google Scholar 

  • Cruz TS, Faria PA, Santana DP, Ferreira JC, Oliveira V, Nascimento OR, Cerchiaro G, Curti C, Nantes IL, Rodrigues T (2010) On the mechanisms of phenothiazine-induced mitochondrial permeability transition: Thiol oxidation, strict Ca2+ dependence, and cyt c release. Biochem Pharmacol 80(8):1284–1295

    Article  PubMed  CAS  Google Scholar 

  • Cunha RL, Gouvea IE, Juliano L (2009a) A glimpse on biological activities of tellurium compounds. An Acad Bras Cienc. 81(3):393–407

    Article  PubMed  CAS  Google Scholar 

  • Cunha RL, Gouvêa IE, Feitosa GP, Alves MF, Brömme D, Comasseto JV, Tersariol IL, Juliano L (2009b) Irreversible inhibition of human cathepsins B, L, S and K by hypervalent tellurium compounds. Biol Chem. 390(11):1205–1212

    Article  PubMed  CAS  Google Scholar 

  • Damveld RA, vanKuyk PA, Arentshorst M, Klis FM, van den Hondel CA, Ram AF (2005) Expression of agsA, one of five 1,3-alpha-d-glucan synthase-encoding genes in Aspergillus niger, is induced in response to cell wall stress. Fungal Genet Biol 42(2):165–177

    Article  PubMed  CAS  Google Scholar 

  • de Oliveira MV, Oliveira AC, Shida CS, de Oliveira RC, Nunes LR (2013) Gene expression modulation by paraquat-induced oxidative stress conditions in Paracoccidioides brasiliensis. Fungal Genet Biol 60:101–109

    Article  PubMed  CAS  Google Scholar 

  • de Paula e Silva AC, Oliveira HC, Silva JF, Sangalli-Leite F, Scorzoni L, Fusco-Almeida AM, Mendes-Giannini MJ (2013) Microplate alamarBlue assay for Paracoccidioides susceptibility testing. J Clin Microbiol 51(4): 1250–1252

  • de Sousa Lima P, Bailão EF, Silva MG, Castro Nda. S, Báo SN, Orlandi I, Vai M, de Almeida Soares CM (2012) Characterization of the Paracoccidioides beta-1,3-glucanosyltransferase family. FEMS Yeast Res 12(6): 685–702

  • Decottignies A, Kolaczkowski M, Balzi E, Goffeau A (1994) Solubilization and characterization of the overexpressed PDR5 multidrug resistance nucleotide triphophatase of yeast. J Biol Chem 269:12797–12803

    PubMed  CAS  Google Scholar 

  • Deisseroth K, Heist EK, Tsein RW (1998) Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392:198–202

    Article  PubMed  CAS  Google Scholar 

  • Delgado-Silva Y, Vaz C, Carvalho-Pereira J, Carneiro C, Nogueira E, Correia A, Carreto L, Silva S, Faustino A, Pais C, Oliveira R, Sampaio P (2014) Participation of Candida albicans transcription factor RLM1 in cell wall biogenesis and virulence. PLoS One 9(1):e86270

    Article  PubMed  PubMed Central  Google Scholar 

  • Desjardins CA, Champion MD, Holder JW, Muszewska A, Goldberg J, Bailão AM, Brigido MM, Ferreira ME, Garcia AM, Grynberg M, Gujja S, Heiman DI, Henn MR, Kodira CD, León-Narváez H, Longo LV, Ma LJ, Malavazi I, Matsuo AL, Morais FV, Pereira M, Rodríguez-Brito S, Sakthikumar S, Salem-Izacc SM, Sykes SM, Teixeira MM, Vallejo MC, Walter ME, Yandava C, Young S, Zeng Q, Zucker J, Felipe MS, Goldman GH, Haas BJ, McEwen JG, Nino-Vega G, Puccia R, San-Blas G, Soares CM, Birren BW, Cuomo CA (2011) Comparative genomic analysis of human fungal pathogens causing paracoccidioidomycosis. PLoS Genet 7(10):e1002345

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Devasahayam G, Scheld WM, Hoffman PS (2010) Newer antibacterial drugs for a new century. Expert Opin Investig Drugs 19(2):215–234

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dichtl K, Ebel F, Dirr F, Routier FH, Heesemann J, Wagener J (2010) Farnesol misplaces tip-localized Rho proteins and inhibits cell wall integrity signalling in Aspergillus fumigatus. Mol Microbiol 76(5):1191–1204

    Article  PubMed  CAS  Google Scholar 

  • Eilam Y (1983) Membrane effects of phenothiazines in yeasts. I. Stimulation of calcium and potassium fluxes. Biochim Biophys Acta 733(2):242–248

    Article  PubMed  CAS  Google Scholar 

  • Eilam Y, Polacheck I, Ben-gigi G, Chernichovsky D (1987) Activity of Phenothiazines against Medically Important Yeasts. Antimicrob Agents Chemother 31(5):834–836

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • El Chamy Maluf S, Melo PM, Varotti FP, Gazarini ML, Cunha RL, Carmona AK (2016) Hypervalent organotellurium compounds as inhibitors of P. falciparum calcium-dependent cysteine proteases. Parasitol Int 65(1): 20–22

  • Ells R, Kemp G, Albertyn J, Kock JL, Pohl CH (2013) Phenothiazine is a potent inhibitor of prostaglandin E2 production by Candida albicans biofilms. FEMS Yeast Res 13(8):849–855

    Article  PubMed  CAS  Google Scholar 

  • Falzon D, Jaramillo E, Schünemann HJ, Arentz M, Bauer M, Bayona J, Blanc L, Caminero JA, Daley CL, Duncombe C, Fitzpatrick C, Gebhard A, Getahun H, Henkens M, Holtz TH, Keravec J, Keshavjee S, Khan AJ, Kulier R, Leimane V, Lienhardt C, Lu C, Mariandyshev A, Migliori GB, Mirzayev F, Mitnick CD, Nunn P, Nwagboniwe G, Oxlade O, Palmero D, Pavlinac P, Quelapio MI, Raviglione MC, Rich ML, Royce S, Rüsch-Gerdes S, Salakaia A, Sarin R, Sculier D, Varaine F, Vitoria M, Walson JL, Wares F, Weyer K, White RA, Zignol M (2011) WHO Guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. World Health Organization

  • Fernandes L, Araújo MA, Amaral A, Reis VC, Martins NF, Felipe MS (2005) Cell signaling pathways in Paracoccidioides brasiliensis—inferred from comparisons with other fungi. Genet Mol Res 4(2):216–231

    PubMed  CAS  Google Scholar 

  • Ferreira ME, Marques E dos R, Malavazi I, Torres I, Restrepo A, Nunes LR, de Oliveira RC, Goldman MH, Goldman GH (2006) Transcriptome analysis and molecular studies on sulfur metabolism in the human pathogenic fungus Paracoccidioides brasiliensis. Mol Genet Genomics 276(5): 450–63

  • Friend DG, Cummins JR (1953) A new anti-emetic drug. JAMA 153: 480

  • Fuchs BB, Mylonakis E (2009) Our paths might cross: the role of the fungal cell wall integrity pathway in stress response and cross talk with other stress response pathways. Eukaryot Cell 8:1616–1625

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM (2003) Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 197(9):1107–1117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goldman GH, dos Reis Marques E, Duarte Ribeiro DC, de Souza Bernardes LA, Quiapin AC, Vitorelli PM, Savoldi M, Semighini CP, de Oliveira RC, Nunes LR, Travassos LR, Puccia R, Batista WL, Ferreira LE, Moreira JC, Bogossian AP, Tekaia F, Nobrega MP, Nobrega FG, Goldman MH (2003) Expressed sequence tag analysis of the human pathogen Paracoccidioides brasiliensis yeast phase: identification of putative homologues of Candida albicans virulence and pathogenicity genes. Eukaryot Cell 2:34–48

    Article  PubMed  PubMed Central  Google Scholar 

  • Gouvea IE, Santos JA, Burlandy FM, Tersariol IL, da Silva EE, Juliano MA, Juliano L, Cunha RL (2011) Poliovirus 3C proteinase inhibition by organotelluranes. Biol Chem. 392(6):587–591

    Article  PubMed  CAS  Google Scholar 

  • Hahn RC, Morato CYT, Santos NL, Ferreira JF, Hamdan JS (2003) Disseminated paracoccidioidomycosis: correlation between clinical and in vitro resistance to ketoconazole and trimethoprim sulphamethoxazole. Mycoses 46(8):342–347

    Article  PubMed  Google Scholar 

  • Hardingham GE, Bading H (1998) Nuclear calcium: a key regulator of gene expression. Biometals 11:345–358

    Article  PubMed  CAS  Google Scholar 

  • Hayes BM, Anderson MA, Traven A, van der Weerden NL, Bleackley MR (2014) Activation of stress signaling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins. Cell Mol Life Sci 71(14):2651–2666

    Article  PubMed  CAS  Google Scholar 

  • Hazen KC (1998) Fungicidal versus fungistatic activity of terbinafine and itraconazole: an in vitro comparison. J Am Acad Dermatol 38:37–41

    Article  Google Scholar 

  • Hector RF (1993) Compounds active against cell walls of medically important fungi. Clin Microbiol Rev 6(1):1–21

    PubMed  PubMed Central  CAS  Google Scholar 

  • Herth W (1980) Calcofluor white and congo red inhibit chitin microfibril assembly of Poteriochromonas: evidence for a gap between polymerization and microfibril formation. J Cell Biol 87:442–450

    Article  PubMed  CAS  Google Scholar 

  • Hiller D, Sanglard D, Morschhauser J (2006) Overexpression of the MDR1gene is sufficient to confer increased resistance to toxic compounds in Candida albicans. Antimicrob Agents Chemother 50:1365–1371

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hung CY, Yu JJ, Lehmann PF, Cole GT (2001) Cloning and expression of the gene which encodes a tube precipitin antigen and wall-associated beta-glucosidase of Coccidioides immitis. Infect Immun 69(4):2211–2222

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jaszczyszyn A, Gąsiorowski K, Świątek P, Malinka W, Cieślik-Boczula K, Petrus J, Czarnik-Matusewicz B (2012) Chemical structure of phenothiazines and their biological activity. Pharmacol Rep. 64(1):16–23

    Article  PubMed  CAS  Google Scholar 

  • Kaatz GW, Moudgal VV, Seo SM, Kristiansen JE (2003) Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chemother 47:719–726

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kolaczkowski M, Michalak K, Motohashi N (2003) Phenothiazines as potent modulators of yeast multidrug resistance. Int J Antimicrob Agents 22(3):279–283

    Article  PubMed  CAS  Google Scholar 

  • Kraus PR, Fox DS, Cox GM, Heitman J (2003) The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function. Mol Microbiol 48(5):1377–1387

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kristiansen JE, Amaral L (1997) The potential management of resistant infections with non-antibiotics. J Antimicrob Chemother 40(3):319–327

    Article  PubMed  CAS  Google Scholar 

  • Kristiansen JE, Hendricks O, Delvin T, Butterworth TS, Aagaard L, Christensen JB, Flores VC, Keyzer H (2007) Reversal of resistance in microorganisms by help of non-antibiotics. J Antimicrob Chemother 59:1271–1279

    Article  PubMed  CAS  Google Scholar 

  • Kumar A, Dhamgaye S, Maurya IK, Singh A, Sharma M, Prasad R (2014) Curcumin targets cell wall integrity via calcineurin-mediated signaling in Candida albicans. Antimicrob. Agents Chemother 58(1): 167–175

  • Kursula P (2014) The many structural faces of calmodulin: a multitasking molecular jackknife. Amino Acids 46(10):2295–2304

    Article  PubMed  CAS  Google Scholar 

  • Latgé JP (2007) The cell wall: a carbohydrate armour for the fungal cell. Mol Microbiol 66:279–290

    Article  PubMed  Google Scholar 

  • Levin DE (2005) Cell wall integrity signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 69(2):262–291

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Levin DE (2011) Regulation of cell wall biogenesis in Saccharomyces cerevisiae: the cell wall integrity signaling pathway. Genetics 189(4):1145–1175

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lewis RE (2011) Current concepts in antifungal pharmacology. Mayo Clin Proc 86(8):805–817

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lima CBC, Arrais-Silva WW, Cunha RLOR, Giorgio S (2009) A novel organotellurium compound (RT-01) as a new antileishmanial agent. Kor J Parasitol. 47(3):213–218

    Article  CAS  Google Scholar 

  • Malheiros SV, De Paula E, Meirelles NC (1998) Contribution of trifluoperazine/lipid ratio and drug ionization to hemolysis. Biochim Biophys Acta 1373(2):332–340

    Article  PubMed  CAS  Google Scholar 

  • Martins M, Viveiros M, Kristiansen JE, Molnar J, Amaral L (2007) The curative activity of thioridazine on mice infected with Mycobacterium tuberculosis. In Vivo 21:771–775

    PubMed  CAS  Google Scholar 

  • Martins VP, Dinamarco TM, Soriani FM, Tudella VG, Oliveira SC, Goldman GH, Curti C, Uyemura SA (2011) Involvement of an alternative oxidase in oxidative stress and mycelium-to-yeast differentiation in Paracoccidioides brasiliensis. Eukaryot Cell 10(2):237–248

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mayer M, Lang PT, Gerber S, Madrid PB, Pinto IG, Guy RK, James TL (2006) Synthesis and testing of a focused phenothiazine library for binding to HIV-1 TAR RNA. Chem Biol 13(9):993–1000

    Article  PubMed  CAS  Google Scholar 

  • Miyazaki T, Inamine T, Yamauchi S, Nagayoshi Y, Saijo T, Izumikawa K, Seki M, Kakeya H, Yamamoto Y, Yanagihara K, Miyazaki Y, Kohno S (2010) Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata. FEMS Yeast Res 10(3):343–352

    Article  PubMed  CAS  Google Scholar 

  • Monte D, Somerville S (2002) Isolation of total RNA from plant tissue using TRizol. In: Bowtell D, Sambrook J (eds) DNA microarrays—a molecular cloning manual. New York: Cold Spring Harbor Laboratory Press, protocol 3, pp 120–123

  • Mucsi I, Molnár J, Motohashi N (2001) Combination of benzo[a]phenothiazines with acyclovir against herpes simplex virus. Int J Antimicrob Agents 18(1):67–72

    Article  PubMed  CAS  Google Scholar 

  • Munro CA (2013) Chapter four—chitin and glucan, the yin and yang of the fungal cell wall, implications for antifungal drug discovery and therapy. In: Sima S, Geoffrey MG (eds) Adv Appl Microbiol, vol 83. Academic Press, London, pp 145–172

    Google Scholar 

  • Nunes LR, Costa De Oliveira RLB, Leite DB, Da Silva VS, Marques ER, Ferreira MES, Ribeiro DCD, Bernardes LAS, Goldman MHS, Puccia R, Travassos LR, Batista WL, Nóbrega MP, Nóbrega FG, Yang DY, Pereira CAB, Goldman GH (2005) Transcriptome analysis of Paracoccidioides brasiliensis cells undergoing the Mycelium-to-Yeast transition. Eukaryot Cell 4:2115–2128

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ordway D, Viveiros M, Leandro C, Arroz MJ, Amaral L (2002) Intracellular activity of clinical concentrations of phenothiazines including thioridiazine against phagocytosed Staphylococcus aureus. Int J Antimicrob Agents 20(1):34–43

    Article  PubMed  CAS  Google Scholar 

  • Ordway D, Viveiros M, Leandro C, Bettencourt R, Almeida J, Martins M, Kristiansen JE, Molnar J, Amaral L (2003) Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 47(3):917–922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pagès JM, Amaral L, Fanning S (2011) An original deal for new molecule: reversal of efflux pump activity, a rational strategy to combat Gram-negative resistant bacteria. Curr Med Chem 18:2969–2980

    Article  PubMed  Google Scholar 

  • Persike DS, Cunha RLOR, Juliano L, Silva IR, Rosim FE, Vignoli T, Cavalheiro EA, Fernandes MJS (2008) Protective effect of the organotelluroxetane RF-07 in the expression of pilocarpine-induced status epilepticus. Neurobiology of Disease 31(1):120–126

    Article  PubMed  CAS  Google Scholar 

  • Piovan L, Alves MF, Juliano L, Brömme D, Cunha RL, Andrade LH (2011) Structure-activity relationships of hypervalent organochalcogenanes as inhibitors of cysteine cathepsins V and S. Bioorg Med Chem. 19(6):2009–2014

    Article  PubMed  CAS  Google Scholar 

  • Pluta K, Morak-Młodawska B, Jeleń M (2011) Recent progress in biological activities of synthesized phenothiazines. Eur J Med Chem 46(8):3179–3189

    Article  PubMed  CAS  Google Scholar 

  • Puccia R, Vallejo MC, Matsuo AL, Longo LV (2011) The paracoccidioides cell wall: past and present layers toward understanding interaction with the host. Front Microbiol. 2:257

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ramos-e-Silva M, Saraiva L, do E (2008) Paracoccidioidomycosis. Dermatol Clin 26(20):257–269

    Article  PubMed  CAS  Google Scholar 

  • Restrepo A, McEwen JG, Castañeda E (2001) The habitat of Paracoccidioides brasiliensis: how far from solving the riddle? Med Mycol 39:233–241

    Article  PubMed  CAS  Google Scholar 

  • Rocha AA, Malavazi I, Goldman GH, Puccia R (2009) Transcription regulation of the Pbgp43 gene by nitrogen in the human pathogen Paracoccidioides brasiliensis. Fungal Genet Biol 46(1):85–93

    Article  PubMed  CAS  Google Scholar 

  • Roemer T, Delaney S, Bussey H (1993) SKN1 and KRE6 define a pair of functional homologs encoding putative membrane proteins involved in beta-glucan synthesis. Mol Cell Biol 13(7):4039–4048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sachlos EL, Risueño RM, Laronde S, Shapovalova Z, Lee JH, Russell J, Malig M, McNicol JD, Fiebig-Comyn A, Graham M, Levadoux-Martin M, Lee JB, Giacomelli AO, Hassell JA, Fischer-Russell D, Trus MR, Foley R, Leber B, Xenocostas A, Brown ED, Collins TJ, Bhatia M (2012) Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 149(6):1284–1297

    Article  PubMed  CAS  Google Scholar 

  • Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, Braisted J, Klapa M, Currier T, Thiagarajan M, Sturn A, Snuffin M, Rezantsev A, Popov D, Ryltsov A, Kostukovich E, Borisovsky I, Liu Z, Vinsavich A, Trush V, Quackenbush J (2003) TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34:374–378

    PubMed  CAS  Google Scholar 

  • Salerno Pimentel IA, Paladi CS, Katz S, de Souza Júdice WA, Cunha RL, Barbiéri CL (2012) In vitro and in vivo activity of an organic tellurium compound on Leishmania (Leishmania) chagasi. PLoS One 7(11):e48780

    Article  PubMed  Google Scholar 

  • San-Blas G, Niño-Vega G (2001) Paracoccidioides brasiliensis: virulence and host response. In: Calderone RA, Cihlar RL (eds) Fungal pathogenesis: principles and clinical applications. Marcel Dekker Inc., New York, pp 205–226

    Google Scholar 

  • San-Blas G, San-Blas F (1994) Biochemistry of Paracoccidioides brasiliensis dimorphism. In: Franco M, Lacaz C, Restrepo-Moreno A, Del Negro A (eds) Paracoccidioidomycosis. CRC Press, Boca Raton, pp 49–66

    Google Scholar 

  • Schuetzer-Muehlbauer M, Willinger B, Krapf G, Enzinger S, Presterl E, Kuchler K (2003) The Candida albicans Cdr2p ATP-binding cassette (ABC) transporter confers resistance to caspofungin. Mol Microbiol 48:225–235

    Article  PubMed  CAS  Google Scholar 

  • Sharma S, Kaur H, Khuller GK (2001) Cell cycle effects of the phenothiazines: trifluoperazine and chlorpromazine in Candida albicans. FEMS Microbiol Lett 199(2):185–190

    Article  PubMed  CAS  Google Scholar 

  • Shikanai-Yatsuda MA, Telles Filho FQ, Mendes RP, Colombo AL, Moretti ML (2006) Consenso em paracoccidioidomicose. Rev Soc Bras Méd Trop 39(3):297–310

    Google Scholar 

  • Slaven JW, Anderson MJ, Sanglard D, Dixon GK, Bille J, Roberts IS, Denning DW (2002) Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate. Fungal Genet Biol 36(3):199–206

    Article  PubMed  CAS  Google Scholar 

  • Sorais F, Barreto L, Leal JA, Bernabé M, San-Blas G, Niño-Veja GA (2010) Cell wall glucan synthases and GTPases in Paracoccidioides brasiliensis. Med Mycol 48(1):35–47

    Article  PubMed  CAS  Google Scholar 

  • Souza KW, Oliveira MCM, Maia RC, Rumjanek VM (2003) Cyclosporin A and analogues as multidrug resistance modulating agents in tumor cell. Rev. Bras. Cancerologia 49(2):103–112

    Google Scholar 

  • Spengler G, Molnar J, Viveiros M, Amaral L (2011) Thioridazine induces apoptosis of multidrug-resistant mouse lymphoma cells transfected with the human ABCB1 and inhibits the expression of P-glycoprotein. Anticancer Res 31(12):4201–4205

    PubMed  CAS  Google Scholar 

  • Thanacoody HK (2007) Thioridazine: resurrection as an antimicrobial agent? Br J Clin Pharmacol 64(5):566–574

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Verna J, Lodder A, Lee K, Vagts A, Ballester R (1997) A family of genes required for maintenance of cell wall integrity and for the stress response in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 94:13804–13809

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Visbal G, San-Blas G, Murgich J, Franco H (2005) Paracoccidioides brasiliensis, paracoccidioidomycosis, and antifungal antibiotics. Curr Drug Targets Infect Disord 5(3):211–226

    Article  PubMed  CAS  Google Scholar 

  • Vitale RG, Afeltra J, Meis JFG, Verweij PE (2007) Activity and post antifungal effect of chlorpromazine and trifluoperazine against Aspergillus, Scedosporium and zygomycetes. Mycoses 50:270–276

    Article  PubMed  CAS  Google Scholar 

  • Viveiros MB, Amaral L (2001) Enhancement of antibiotic activity against polydrug-resistant Mycobacterium tuberculosis by phenothiazines. Int J Antimicrob Agents 17:225–228

    Article  PubMed  CAS  Google Scholar 

  • Walker LA, Munro CA, de Bruijn I, Lenardon MD, McKinnon A, Gow NA (2008) Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog 4(4):e1000040

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Casadevall A (1996) Susceptibility of melanized and nonmelanized Cryptococcus neoformans to the melanin-binding compounds trifluoperazine and chloroquine. Antimicrob Agents Chemother 40(3):541–545

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wang E, Marincola FM (2002) In: Bowtell D, Sambrook J (eds) DNA Microarrays. Cold Spring Harbor Laboratory Press, Cold, Spring Harbor, New York, pp 204–213

    Google Scholar 

  • Warman AJ, Rito TS, Fisher NE, Moss DM, Berry NG, O’Neill PM, Ward SA, Biagini GA (2013) Antitubercular pharmacodynamics of phenothiazines. J Antimicrob Chemother 68(4):869–880

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wood PJ (1980) Specificity in the interaction of direct dyes with polysaccharides. Carbohydr Res 81:271–287

    Article  Google Scholar 

  • Yamaguchi MU, Silva APB, Ueda-Nakamura T, Dias Filho BP, Silva CC, Nakamura CV (2009) Effects of a thiosemicarbazide camphene derivative on Trichophyton mentagrophytes. Molecules 17:1796–1807

    Article  Google Scholar 

  • Zamani A, Jeihanipour A, Edebo L, Niklasson C, Taherzadeh MJ (2008) Determination of glucosamine and N-acetyl glucosamine in fungal cell walls. J Agric Food Chem 56:8314–8318

    Article  PubMed  CAS  Google Scholar 

  • Zambuzzi-Carvalho PF, Tomazetti PK, Santos SC, Ferri PH, Borges CL, Martins WS, de Almeida Soares CM, Pereira M (2013) Transcriptional profile of Paracoccidioides induced by oenothein B, a potential antifungal agent from the Brazilian Cerrado plant Eugenia uniflora. BMC Microbiol 13:227

    Article  PubMed  PubMed Central  Google Scholar 

  • Zeitlinger MA, Derendorf H, Mouton JW, Cars O, Craig WA, Andes D, Theuretzbacher U (2011) Protein binding: do we ever learn? Antimicrob Agents Chemother 55(7):3067–3074

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zeni G, Chieffi A, Cunha RLOR, Zukerman-Schpector J, Stefani HA, Comasseto JV (1999) Addition reaction of p-methoxyphenyltellurium trichloride to 3-hydroxy alkynes. Organometallics 18:803–806

    Article  CAS  Google Scholar 

  • Zong D, Zielinska-Chomej K, Juntti T, Mörk B, Lewensohn R, Hååg P, Viktorsson K (2014) Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer. Cell Death Dis 13(5):e1111

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP [Grant numbers #09/50114-7, #09/50115-3, #06/0995-9, #12/12247-8]; and Fundação de Amparo ao Ensino e à Pesquisa. Some of the authors were also supported by scholarship grants from the following Brazilian agencies: CAPES (ACO, DLJ, VCA, DLSR and FBM), CNPq (DAB and ROVB) and FAPESP (DSS).

Author information

Author notes

    Authors and Affiliations

    1. Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes (UMC), Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, CEP 08780-911, Brazil

      Daniela Leite Jabes, Ana Claudia de Freitas Oliveira, Valquíria Campos Alencar, Fabiano Bezerra Menegidio, Daiene Souza Santos, David Aciole Barbosa, Renata Ozelami Vilas Boas & Regina Costa de Oliveira

    2. Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Rua Santa Adélia, 166, Santo André, SP, CEP 09210-170, Brazil

      Débora Liliane Souza Reno, Rodrigo Luiz de Oliveira Rodrigues Cunha,  Tiago Rodrigues & Luiz R. Nunes

    Authors
    1. Daniela Leite Jabes
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ana Claudia de Freitas Oliveira
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Valquíria Campos Alencar
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Fabiano Bezerra Menegidio
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Débora Liliane Souza Reno
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Daiene Souza Santos
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. David Aciole Barbosa
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Renata Ozelami Vilas Boas
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Rodrigo Luiz de Oliveira Rodrigues Cunha
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Tiago Rodrigues
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Regina Costa de Oliveira
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Luiz R. Nunes
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Luiz R. Nunes.

    Ethics declarations

    Conflict of interest

    All authors declare that they have no conflict of interest.

    Ethical approval

    This article does not contain any studies with human participants or animals performed by any of the authors.

    Additional information

    Communicated by J. Perez-Martin.

    Daniela Leite Jabes and Ana Claudia de Freitas Oliveira contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (TXT 206 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Jabes, D.L., de Freitas Oliveira, A.C., Alencar, V.C. et al. Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis . Mol Genet Genomics 291, 1347–1362 (2016). https://doi.org/10.1007/s00438-016-1184-1

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00438-016-1184-1

    Keywords

    Search

    Navigation