Abstract
Drug resistance mechanisms in the commensal human pathogen Candida albicans are continually evolving. Over time, Candida species have implemented diverse strategies to vanquish the effects of various classes of drugs, thereby emanating as a serious life threat. Apart from the repertoire of well-established strategies, which predominantly comprise permeability constraints, increased drug efflux or compromised drug import, alteration, overexpression of drug targets, and chromosome duplication, C. albicans has evolved novel regulatory mechanisms of drug resistance. For instance, recent evidences point to newer circuitry involving different mediators of the stress-responsive machinery of oxidative, osmotic, thermal, nitrosative, and nutrient limitation, which contribute to the emergence of drug resistance. Contemporary advances in genome-wide studies of transcription factors, for instance, the Zn2Cys6 transcription factors, TAC1 (transcriptional activator of CDR) in Candida albicans, or YRR1 in yeast have made it feasible to dissect their involvement for the elucidation of unexplored regulatory network of drug resistance. The coordination of implementers of the conventional and nonconventional drug resistance strategies provides robustness to this commensal human pathogen. In this review, we shed light not only on the established strategies of antifungal resistance but also discuss emerging cellular circuitry governing drug resistance of this human pathogen.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsNotes
- 1.
Three stresses described in Fig. 6.2:
-
(1)
Oxidative Stress
Oxidative stress regulator, Cap1, induces the overexpression of MDR1 by recruiting Ada2, a subunit of the SAGA/ADA coactivator complex on MDR1 promoter, thereby leading to an activation of drug resistance genes. Cap1 and Mrr1, both bind to the MDR1 promoter, and cooperate to promote MDR1 upregulation in response to inducing chemicals.
-
(2)
Metal Stress
-
(i)
Iron depletion leads to downregulation of ERG11 gene, along with a parallel upregulation of ERG3 gene. The downregulation of ERG11 increases the membrane fluidity leading to a rise in passive drug diffusion, and hence increased drug susceptibility. The increase in Erg3 levels leads to accumulation of toxic sterols on the cell membrane resulting in cell death.
-
(ii)
Magnesium depletion influences drug resistance majorly toward echinocandins. Its deficiency influences mutations in the histidine kinase gene, NIK1, thereby blocks the activation of Hog1 in response to the drug, enhancing caspofungin activity.
-
(iii)
Calcium depletion either by chelating extracellular calcium with ethylene diamine tetra-acetic acid (EDTA) or the inhibition of calcium importers with benidipine and nifedipine, leading to enhanced azole activity against C. albicans.
-
(i)
-
(3)
Heat Stress
-
(i)
By binding to and chaperoning calcineurin, the thermal stress regulator, Hsp90, regulates calcineurin-dependent stress responses, thereby enabling the cell to survive the membrane stress induced by azoles. Several downstream effectors of calcineurin mediate cellular responses to azoles, including the transcription factor Crz1.
-
(ii)
Heat shock factor 1, Hsf1, has been observed to be crucial for the survival of C. albicans in the presence of various classes of drugs. The susceptibility shown toward certain classes of drugs was seen to be iron dependent.
-
(i)
-
(1)
References
Alarco A, Raymond M, Ave P (1999) The bZip transcription factor cap1p is involved in multidrug resistance and oxidative stress response in candida albicans. 181:700–708
Anderson TM, Clay MC, Cioffi AG et al (2014) Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol 10:400–406
Banerjee A, Haseeb A, Kumari A, Moreno A, Falson P (2018) W1038 near D-loop of NBD2 is a focal point for inter-domain communication in multidrug transporter Cdr1 of Candida albicans. BBA - Biomembr 1860:965–972
Barchiesi F, Calabrese D, Sanglard D, Falconi Di Francesco L, Caselli F, Giannini D, Giacometti A, Gavaudan S, Scalise G (2000) Experimental induction of fluconazole resistance in Candida tropicalis ATCC 750. Antimicrob Agents Chemother 44:1578–1584
Brown AJP, Cowen LE, di Pietro A, Quinn J (2017) Stress Adaptation. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.funk-0048-2016
Butts A, Palmer GE, Rogers PD (2017) Antifungal adjuvants: Preserving and extending the antifungal arsenal. Virulence 8:198–210
Chauhan N, Latge J-P, Calderone R (2006) Signalling and oxidant adaptation in Candida albicans and Aspergillus fumigatus. Nat Rev Microbiol 4:435–444
Chen KH, Miyazaki T, Tsai HF, Bennett JE (2007) The bZip transcription factor Cgap1p is involved in multidrug resistance and required for activation of multidrug transporter gene CgFLR1 in Candida glabrata. Gene 386:63–72
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
Chen C, Pande K, French SD, Tuch BB, Noble SM (2011) An iron homeostasis regulatory circuit with reciprocal roles in candida albicans commensalism and pathogenesis. Cell Host Microbe 10:118–135
Citiulo F, Jacobsen ID, Miramón P, Schild L, Brunke S, Zipfel P, Brock M, Hube B, Wilson D (2012) Candida albicans scavenges host zinc via Pra1 during endothelial invasion. PLoS Pathog. https://doi.org/10.1371/journal.ppat.1002777
Cornet M, Gaillardin C (2014) pH signaling in human fungal pathogens: a new target for antifungal strategies. Eukaryot Cell 13:342–352
Coste A, Turner V, Ischer F, Morschhauser J, Forche A, Selmecki A, Berman J, Bille J, Sanglard D (2006) A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 172:2139–2156
Cowen LE (2008) The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat Rev Microbiol 6:187–198
Cowen LE (2009) Hsp90 orchestrates stress response signaling governing fungal drug resistance. PLoS Pathog 5:8–10
Cowen LE, Lindquist S (2005) Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science (80-) 309:2185–2189
Cowen LE, Steinbach WJ (2008) Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance. Eukaryot Cell 7:747–764
Cowen LE, Carpenter AE, Matangkasombut O, Fink GR, Lindquist S (2006) Genetic Architecture of Hsp90-Dependent Drug Resistance. Eukaryot Cell 5:2184–2188
Cuéllar-Cruz M, Briones-Martin-del-Campo M, Cañas-Villamar I, Montalvo-Arredondo J, Riego-Ruiz L, Castaño I, De Las Peñas A (2008) High resistance to oxidative stress in the fungal pathogen Candida glabrata is mediated by a single catalase, Cta1p, and is controlled by the transcription factors Yap1p, Skn7p, Msn2p, and Msn4p. Eukaryot Cell 7:814–825
Dantas ADS, Day A, Ikeh M, Kos I, Achan B, Quinn J (2015) Oxidative stress responses in the human fungal pathogen, Candida albicans. Biomolecules 5:142–165
Dhamgaye S, Devaux F, Vandeputte P, Khandelwal NK, Sanglard D, Mukhopadhyay G, Prasad R (2014) Molecular mechanisms of action of herbal antifungal alkaloid berberine, in Candida Albicans. PLoS ONE 9:e104554
Dunkel N, Liu TT, Barker KS, Homayouni R, Morschhäuser J, Rogers PD (2008) A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate. Eukaryot Cell 7:1180–1190
Garcia-Effron G, Dilger A, Alcazar-Fuoli L, Park S, Mellado E, Perlin DS (2008) Rapid detection of triazole antifungal resistance in Aspergillus fumigatus. J Clin Microbiol 46:1200–1206
Garcia-Effron G, Park S, Perlin DS (2009) Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints. Antimicrob Agents Chemother 53:112–122
Gaur M, Puri N, Manoharlal R, Rai V, Mukhopadhayay G, Choudhury D, Prasad R (2008) MFS transportome of the human pathogenic yeast Candida albicans. BMC Genom 9:579
Hameed S, Dhamgaye S, Singh A, Goswami SK, Prasad R (2011) Calcineurin signaling and membrane lipid homeostasis regulates iron mediated multidrug resistance mechanisms in Candida albicans. PLoS ONE 6:e18684
Holmes AR, Lin Y-H, Niimi K, Lamping E, Keniya M, Niimi M, Tanabe K, Monk BC, Cannon RD (2008) ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates. Antimicrob Agents Chemother 52:3851–3862
Hoot SJ, Smith AR, Brown RP, White TC (2011) An A643 V amino acid substitution in Upc2p contributes to azole resistance in well-characterized clinical isolates of Candida albicans. Antimicrob Agents Chemother 55:940–942
Jamieson DJ (1998) Oxidative Stress Responses of the Yeast Saccharomyces cerevisiae. 1527:1511–1527
Jensen RH, Astvad KMT, Silva LV, Sanglard D, Jorgensen R, Nielsen KF, Mathiasen EG, Doroudian G, Perlin DS, Arendrup MC (2015) Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations. J Antimicrob Chemother 70:2551–2555
Kanafani ZA, Perfect JR (2008) Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis 46:120–128
Kehl-Fie TE, Skaar EP (2010) Nutritional immunity beyond iron: a role for manganese and zinc. Curr Opin Chem Biol 14:218–224
Kelly SL, Lamb DC, Corran AJ, Baldwin BC, Kelly DE (1995) Mode of Action and Resistance to Azole Antifungals Associated with the Formation of 14α-Methylergosta-8,24(28)-dien-3β,6α-diol. Biochem Biophys Res Commun 207:910–915
Khandelwal NK, Chauhan N, Sarkar P, et al (2017) Azole resistance in a Candida albicans mutant lacking the ABC transporter CDR6/ROA1 depends on TOR signaling. J Biol Chem. https://doi.org/10.1074/jbc.m117.807032
Lafayette SL, Collins C, Zaas AK, Schell WA, Betancourt-Quiroz M, Leslie Gunatilaka AA, Perfect JR, Cowen LE (2010) PKC signaling regulates drug resistance of the fungal pathogen candida albicans via circuitry comprised of mkc1, calcineurin, and hsp90. PLoS Pathog 6:79–80
Leach MD, Budge S, Walker L, Munro C, Cowen LE, Brown AJP (2012) Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast. PLoS Pathog 8:e1003069
Li R, Kumar R, Tati S, Puri S, Edgerton M (2013) Candida albicans flu1-mediated efflux of salivary histatin 5 reduces its cytosolic concentration and fungicidal activity. Antimicrob Agents Chemother 57:1832–1839
Liu S, Yue L, Gu W, Li X, Zhang L, Sun S (2016) Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans. PLoS ONE 11:e0150859
Maebashi K, Kudoh M, Nishiyama Y, Makimura K, Uchida K, Mori T, Yamaguchi H (2002) A novel mechanism of fluconazole resistance associated with fluconazole sequestration in Candida albicans isolates from a myelofibrosis patient. Microbiol Immunol 46:317–326
Mandal A, Kumar A, Singh A, Lynn AM, Kapoor K, Prasad R (2012) A key structural domain of the Candida albicans Mdr1 protein. Biochem J 445:313–322
Mansfield BE, Oltean HN, Oliver BG, Hoot SJ, Leyde SE, Hedstrom L, White TC (2010) Azole drugs are imported by facilitated diffusion in Candida albicans and other pathogenic fungi. PLoS Pathog 6:e1001126
Marichal P, Koymans L, Willemsens S, Bellens D, Verhasselt P, Luyten W, Borgers M, Ramaekers FCS, Odds FC, Vanden Bossche H (1999) Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology 145 Pt 1:2701–2713
Martel CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AGS, Rolley N, Kelly DE, Kelly SL (2010a) Identification and characterization of four azole-resistant erg3 mutants of Candida albicans. Antimicrob Agents Chemother 54:4527–4533
Martel CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AGS, Kelly DE, Kelly SL (2010b) A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14alpha-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B. Antimicrob Agents Chemother 54:3578–3583
Moran GP, Sanglard D, Donnelly SM, Shanley DB, Sullivan DJ, Coleman DC (1998) Identification and expression of multidrug transporters responsible for fluconazole resistance in Candida dubliniensis. Antimicrob Agents Chemother 42:1819–1830
Morio F, Pagniez F, Lacroix C, Miegeville M, Le Pape P (2012) Amino acid substitutions in the Candida albicans sterol Δ5,6-desaturase (Erg3p) confer azole resistance: characterization of two novel mutants with impaired virulence. J Antimicrob Chemother 67:2131–2138
Morschhäuser J, Barker KS, Liu TT, BlaB-Warmuth J, Homayouni R, Rogers PD (2007) The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog 3:e164
Nair R, Shariq M, Dhamgaye S, Mukhopadhyay CK, Shaikh S, Prasad R (2017) Non-heat shock responsive roles of HSF1 in Candida albicans are essential under iron deprivation and drug defense. Biochim Biophys Acta - Mol Cell Res 1864:345–354
Nair R, Khandelwal NK, Shariq M, Redhu AK, Gaur NA, Shaikh S, Prasad R (2018) Identification of genome-wide binding sites of heat shock factor 1, Hsf1, under basal conditions in the human pathogenic yeast. Candida albicans. AMB Express 8:116
Nicholls S, Leach MD, Priest CL, Brown AJP (2009) Role of the heat shock transcription factor, Hsf1, in a major fungal pathogen that is obligately associated with warm-blooded animals. Mol Microbiol 74:844–861
Nicholls S, MacCallum DM, Kaffarnik FAR, Selway L, Peck SC, Brown AJP (2011) Activation of the heat shock transcription factor Hsf1 is essential for the full virulence of the fungal pathogen Candida albicans. Fungal Genet Biol 48:297–305
Pais P, Costa C, Pires C, Shimizu K, Chibana H, Teixeira MC (2016) Membrane Proteome-Wide Response to the Antifungal Drug Clotrimazole in Candida glabrata: Role of the Transcription Factor CgPdr1 and the Drug:H + Antiporters CgTpo1_1 and CgTpo1_2. Mol Cell Proteomics 15:57–72
Polvi EJ, Averette AF, Lee SC, Kim T, Bahn YS, Veri AO, Robbins N, Heitman J, Cowen LE (2016a) Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis. PLoS Genet 12:1–35
Polvi EJ, Averette AF, Lee SC, Kim T, Bahn Y, Veri AO, Robbins N, Heitman J, Cowen LE (2016) Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis. 1–35
Posteraro B, Sanguinetti M, Sanglard D, La Sorda M, Boccia S, Romano L, Morace G, Fadda G (2003) Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter-encoding gene, CnAFR1, involved in the resistance to fluconazole. Mol Microbiol 47:357–371
Prasad T, Chandra A, Mukhopadhyay CK, Prasad R (2006) Unexpected link between iron and drug resistance of Candida spp.: iron depletion enhances membrane fluidity and drug diffusion, leading to drug-susceptible cells. Antimicrob Agents Chemother 50:3597–3606
Prasad R, Banerjee A, Khandelwal NK, Dhamgaye S (2015) The ABCs of Candida albicans Multidrug Transporter Cdr1. Eukaryot Cell 14:1154–1164
Prasad R, Banerjee A, Shah AH (2017) Resistance to antifungal therapies. Essays Biochem 61:157–166
Ramírez-Zavala B, Mogavero S, Schöller E, Sasse C, Rogers PD, Morschhäuser J (2014) SAGA/ADA complex subunit Ada2 is required for Cap1- But not Mrr1-mediated upregulation of the Candida albicans multidrug efflux pump MDR1. Antimicrob Agents Chemother 58:5102–5110
Rawal MK, Khan MF, Kapoor K et al (2013) Insight into pleiotropic drug resistance ATP-binding cassette pump drug transport through mutagenesis of Cdr1p transmembrane domains. J Biol Chem 288:24480–24493
Redhu AK, Khandelwal NK, Banerjee A, Moreno A, Falson P, Prasad R (2016) pHluorin enables insights into the transport mechanism of antiporter Mdr 1: R215 is critical for drug/H + antiport. Biochem J 473:3127–3145
Redhu AK, Banerjee A, Shah AH, Moreno A, Rawal MK, Nair R, Falson P, Prasad R (2018) Molecular Basis of Substrate Polyspecificity of the Candida albicans Mdr1p Multidrug/H(+) Antiporter. J Mol Biol 430:682–694
Robbins N, Caplan T, Cowen LE (2017) Molecular evolution of antifungal drug resistance
Rodero L, Mellado E, Rodriguez AC, Salve A, Guelfand L, Cahn P, Cuenca-Estrella M, Davel G, Rodriguez-Tudela JL (2003) G484S amino acid substitution in lanosterol 14-alpha demethylase (ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate. Antimicrob Agents Chemother 47:3653–3656
Rognon B, Kozovska Z, Coste AT, Pardini G, Sanglard D (2006) Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans, a major facilitator transporter involved in azole resistance. Microbiology 152:3701–3722
Sanglard D (2016) Emerging Threats in Antifungal-Resistant Fungal Pathogens. Front Med 3:11
Sanglard D (2017) Mechanisms of Drug Resistance in Candida albicans. In: Prasad R (ed) Candida albicans cellular and molecular biology. Springer International Publishing, Cham, pp 287–311
Sanguinetti M, Posteraro B, La Sorda M, Torelli R, Fiori B, Santangelo R, Delogu G, Fadda G (2006) Role of AFR1, an ABC transporter-encoding gene, in the in vivo response to fluconazole and virulence of Cryptococcus neoformans. Infect Immun 74:1352–1359
Shah AH, Rawal MK, Dhamgaye S, Komath SS, Saxena AK, Prasad R (2015) Mutational Analysis of Intracellular Loops Identify Cross Talk with Nucleotide Binding Domains of Yeast ABC Transporter Cdr1p. Sci Rep 5:11211
Shapiro RS, Robbins N, Cowen LE (2011) Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol Mol Biol Rev 75:213–267
Shapiro RS, Zaas AK, Betancourt-Quiroz M, Perfect JR, Cowen LE (2012) The Hsp90 co-chaperone Sgt1 governs Candida albicans morphogenesis and drug resistance. PLoS ONE 7:e44734
Shekhar-Guturja T, Gunaherath GMKB, Wijeratne EMK et al (2016) Dual action antifungal small molecule modulates multidrug efflux and TOR signaling. Nat Chem Biol 12:867–875
Singh SD, Robbins N, Zaas AK, Schell WA, Perfect JR, Cowen LE (2009) Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog 5:e1000532
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 36:199–206
Taff HT, Mitchell KF, Edward JA, Andes DR (2013) Mechanisms of Candida biofilm drug resistance. Futur Microbiol 8:1325–1337
Tchenio T, Havard M, Martinez LA, Dautry F (2006) Heat shock-independent induction of multidrug resistance by heat shock factor 1. Mol Cell Biol 26:580–591
Vasicek EM, Berkow EL, Flowers SA, Barker KS, David Rogers P (2014) UPC2 is universally essential for azole antifungal resistance in Candida albicans. Eukaryot Cell 13:933–946
White TC (1997) Increased mRNA levels of ERG16, CDR, and MDR1 correlate, with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob Agents Chemother 41:1482–1487
White TC, Holleman S, Dy F, Mirels LF, Stevens DA (2002) Resistance mechanisms in clinical isolates of Candida albicans. Antimicrob Agents Chemother 46:1704–1713
Wong ILK, Chow LMC (2006) The role of Leishmania enriettii multidrug resistance protein 1 (LeMDR1) in mediating drug resistance is iron-dependent. Mol Biochem Parasitol 150:278–287
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Prasad, R., Nair, R., Banerjee, A. (2019). Emerging Mechanisms of Drug Resistance in Candida albicans. In: Sá-Correia, I. (eds) Yeasts in Biotechnology and Human Health. Progress in Molecular and Subcellular Biology, vol 58. Springer, Cham. https://doi.org/10.1007/978-3-030-13035-0_6
Download citation
DOI: https://doi.org/10.1007/978-3-030-13035-0_6
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-13034-3
Online ISBN: 978-3-030-13035-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)