Harnessing Metal Homeostasis Offers Novel and Promising Targets Against Candida albicans

Author(s): Saif Hameed*, Sandeep Hans, Shweta Singh, Zeeshan Fatima*

Journal Name: Current Drug Discovery Technologies

Volume 17 , Issue 4 , 2020

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Graphical Abstract:


Fungal infections, particularly of Candida species, which are the commensal organisms of human, are one of the major debilitating diseases in immunocompromised patients. The limited number of antifungal drugs available to treat Candida infections, with the concomitant increasing incidence of multidrug-resistant (MDR) strains, further worsens the therapeutic options. Thus, there is an urgent need for the better understanding of MDR mechanisms, and their reversal, by employing new strategies to increase the efficacy and safety profiles of currently used therapies against the most prevalent human fungal pathogen, Candida albicans. Micronutrient availability during C. albicans infection is regarded as a critical factor that influences the progression and magnitude of the disease. Intracellular pathogens colonize a variety of anatomical locations that are likely to be scarce in micronutrients, as a defense strategy adopted by the host, known as nutritional immunity. Indispensable critical micronutrients are required both by the host and by C. albicans, especially as a cofactor in important metabolic functions. Since these micronutrients are not freely available, C. albicans need to exploit host reservoirs to adapt within the host for survival. The ability of pathogenic organisms, including C. albicans, to sense and adapt to limited micronutrients in the hostile environment is essential for survival and confers the basis of its success as a pathogen. This review describes that micronutrients availability to C. albicans is a key attribute that may be exploited when one considers designing strategies aimed at disrupting MDR in this pathogenic fungi. Here, we discuss recent advances that have been made in our understanding of fungal micronutrient acquisition and explore the probable pathways that may be utilized as targets.

Keywords: MDR, micronutrient, iron, zinc, copper, calcium, magnesium and manganese.

Wenzel RP, Gennings C. Bloodstream infections due to Candida species in the intensive care unit: identifying especially high-risk patients to determine prevention strategies. Clin Infect Dis 2005; 41(Suppl. 6): S389-93.
[http://dx.doi.org/10.1086/430923] [PMID: 16108005]
Singh S, Fatima Z, Hameed S. Predisposing factors endorsing Candida infections. Infez Med 2015; 23(3): 211-23.
[PMID: 26397289]
Arendrup MC, Patterson TF. Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment J Infect Dis 2017; 216(suppl_3): S445-51.
[http://dx.doi.org/10.1093/infdis/jix131] [PMID: 28911043]
Tanwar J, Das S, Fatima Z, Hameed S. Multidrug resistance: an emerging crisis. Interdiscip Perspect Infect Dis 2014. 2014541340
[http://dx.doi.org/10.1155/2014/541340] [PMID: 25140175]
Jensen RH, Astvad KM, Silva LV, et al. Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations. J Antimicrob Chemother 2015; 70(9): 2551-5.
[http://dx.doi.org/10.1093/jac/dkv140] [PMID: 26017038]
Prasad T, Hameed S, Manoharlal R, et al. Morphogenic regulator EFG1 affects the drug susceptibilities of pathogenic Candida albicans. FEMS Yeast Res 2010; 10(5): 587-96.
[http://dx.doi.org/10.1111/j.1567-1364.2010.00639.x] [PMID: 20491944]
Kobayashi D, Kondo K, Uehara N, et al. Endogenous reactive oxygen species is an important mediator of miconazole antifungal effect. Antimicrob Agents Chemother 2002; 46(10): 3113-7.
[http://dx.doi.org/10.1128/AAC.46.10.3113-3117.2002] [PMID: 12234832]
White TC, Holleman S, Dy F, Mirels LF, Stevens DA. Resistance mechanisms in clinical isolates of Candida albicans. Antimicrob Agents Chemother 2002; 46(6): 1704-13.
[http://dx.doi.org/10.1128/AAC.46.6.1704-1713.2002] [PMID: 12019079]
Prasad R, Gaur NA, Gaur M, Komath SS. Efflux pumps in drug resistance of Candida. Infect Disord Drug Targets 2006; 6(2): 69-83.
[http://dx.doi.org/10.2174/187152606784112164] [PMID: 16789872]
Hameed S, Fatima Z. Novel Regulatory Mechanisms of Pathogenicity and Virulence to Combat MDR in Candida albicans. Int J Microbiol 2013; •••2013240209
[http://dx.doi.org/10.1155/2013/240209] [PMID: 24163696]
Hood MI, Skaar EP. Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol 2012; 10(8): 525-37.
[http://dx.doi.org/10.1038/nrmicro2836] [PMID: 22796883]
Posey JE, Gherardini FC. Lack of a role for iron in the Lyme disease pathogen. Science 2000; 288(5471): 1651-3.
[http://dx.doi.org/10.1126/science.288.5471.1651] [PMID: 10834845]
Brzóska K, Meczyńska S, Kruszewski M. Iron-sulfur cluster proteins: electron transfer and beyond. Acta Biochim Pol 2006; 53(4): 685-91.
[http://dx.doi.org/10.18388/abp.2006_3296] [PMID: 17143336]
Halliwell B, Gutteridge JM. Use of monoclonal antibody panel to identify malignant cells in cerebrospinal fluid. Lancet 1984; 10: 1095.
Hameed S, Fatima Z. Struggle for iron: a key attribute for combating MultiDrug Resistance in human pathogen Candida albicans. IJSRP 2012; 2: 1-5.
Kuznets G, Vigonsky E, Weissman Z, et al. A relay network of extracellular heme-binding proteins drives C. albicans iron acquisition from hemoglobin. PLoS Pathog 2014; 10(10)e1004407
[http://dx.doi.org/10.1371/journal.ppat.1004407] [PMID: 25275454]
Heymann P, Gerads M, Schaller M, Dromer F, Winkelmann G, Ernst JF. The siderophore iron transporter of Candida albicans (Sit1p/Arn1p) mediates uptake of ferrichrome-type siderophores and is required for epithelial invasion. Infect Immun 2002; 70(9): 5246-55.
[http://dx.doi.org/10.1128/IAI.70.9.5246-5255.2002] [PMID: 12183576]
Lee JH, Han Y. Candida albicans can utilize siderophore during candidastasis caused by apotransferrin. Arch Pharm Res 2006; 29(3): 249-55.
[http://dx.doi.org/10.1007/BF02969401] [PMID: 16596999]
Knight SA, Vilaire G, Lesuisse E, Dancis A. Iron acquisition from transferrin by Candida albicans depends on the reductive pathway. Infect Immun 2005; 73(9): 5482-92.
[http://dx.doi.org/10.1128/IAI.73.9.5482-5492.2005] [PMID: 16113264]
Ramanan N, Wang Y. A high-affinity iron permease essential for Candida albicans virulence. Science 2000; 288(5468): 1062-4.
[http://dx.doi.org/10.1126/science.288.5468.1062] [PMID: 10807578]
Almeida RS, Brunke S, Albrecht A, et al. the hyphal-associated adhesin and invasin Als3 of Candida albicans mediates iron acquisition from host ferritin. PLoS Pathog 2008; 4(11)e1000217
[http://dx.doi.org/10.1371/journal.ppat.1000217] [PMID: 19023418]
Weissman Z, Shemer R, Conibear E, Kornitzer D. An endocytic mechanism for haemoglobin-iron acquisition in Candida albicans. Mol Microbiol 2008; 69(1): 201-17.
[http://dx.doi.org/10.1111/j.1365-2958.2008.06277.x] [PMID: 18466294]
Baek YU, Li M, Davis DA. Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors. Eukaryot Cell 2008; 7(7): 1168-79.
[http://dx.doi.org/10.1128/EC.00108-08] [PMID: 18503007]
Hameed S, Dhamgaye S, Singh A, Goswami SK, Prasad R. Calcineurin signaling and membrane lipid homeostasis regulates iron mediated multidrug resistance mechanisms in Candida albicans. PLoS One 2011; 6(4)e18684
[http://dx.doi.org/10.1371/journal.pone.0018684] [PMID: 21533276]
Kobayashi T, Kakeya H, Miyazaki T, et al. Synergistic antifungal effect of lactoferrin with azole antifungals against Candida albicans and a proposal for a new treatment method for invasive candidiasis. Jpn J Infect Dis 2011; 64(4): 292-6.
[PMID: 21788703]
Fiori A, Van Dijck P. Potent synergistic effect of doxycycline with fluconazole against Candida albicans is mediated by interference with iron homeostasis. Antimicrob Agents Chemother 2012; 56(7): 3785-96.
[http://dx.doi.org/10.1128/AAC.06017-11] [PMID: 22564841]
Puri S, Friedman J, Saraswat D, et al. Candida albicans Shed Msb2 and Host Mucins Affect the Candidacidal Activity of Salivary Hst 5. Pathogens 2015; 4(4): 752-63.
[http://dx.doi.org/10.3390/pathogens4040752] [PMID: 26529023]
Jia C, Zhang K, Yu Q, et al. Tfp1 is required for ion homeostasis, fluconazole resistance and N-Acetylglucosamine utilization in Candida albicans. Biochim Biophys Acta 2015; 1853(10 Pt A): 2731-44.
[http://dx.doi.org/10.1016/j.bbamcr.2015.08.005] [PMID: 26255859]
Ansari MA, Fatima Z, Hameed S. Mechanistic insights into the mode of action of anticandidal sesamol. Microb Pathog 2016; 98: 140-8.
[http://dx.doi.org/10.1016/j.micpath.2016.07.004] [PMID: 27392701]
Ansari MA, Fatima Z, Hameed S. Anticandidal Effect and Mechanisms of Monoterpenoid, Perillyl Alcohol against Can-dida albicans. PLoS One 2016; 11(9)e0162465
Ansari MA, Fatima Z, Hameed S. Sesamol: a natural phe-nolic compound with promising anticandidal potential. J. Pathog 2014.
Singh S, Fatima Z, Hameed S. Insights into the mode of action of anticandidal herbal monoterpenoid geraniol reveal disruption of multiple MDR mechanisms and virulence attributes in Candida albicans. Arch Microbiol 2016; 198(5): 459-72.
[http://dx.doi.org/10.1007/s00203-016-1205-9] [PMID: 26935560]
Tripathi SK, Xu T, Feng Q, et al. Two plant-derived aporphinoid alkaloids exert their antifungal activity by disrupting mitochondrial iron-sulfur cluster biosynthesis. J Biol Chem 2017; 292(40): 16578-93.
[http://dx.doi.org/10.1074/jbc.M117.781773] [PMID: 28821607]
Mohammad H, Elghazawy NH, Eldesouky HE, et al. Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis. ACS Infect Dis 2018; 4(3): 403-14.
[http://dx.doi.org/10.1021/acsinfecdis.7b00215] [PMID: 29370698]
Yu Q, Dong Y, Xu N, et al. A novel role of the ferric reductase Cfl1 in cell wall integrity, mitochondrial function, and invasion to host cells in Candida albicans. FEMS Yeast Res 2014; 14(7): 1037-47.
[http://dx.doi.org/10.1111/1567-1364.12194] [PMID: 25130162]
Balhara M, Chaudhary R, Ruhil S, et al. Siderophores; iron scavengers: the novel & promising targets for pathogen specific antifungal therapy. Expert Opin Ther Targets 2016; 20(12): 1477-89.
[http://dx.doi.org/10.1080/14728222.2016.1254196] [PMID: 27797604]
Xu N, Dong Y, Cheng X, et al. Cellular iron homeostasis mediated by the Mrs4-Ccc1-Smf3 pathway is essential for mitochondrial function, morphogenesis and virulence in Candida albicans. Biochim Biophys Acta 2014; 1843(3): 629-39.
[http://dx.doi.org/10.1016/j.bbamcr.2013.12.009] [PMID: 24368185]
Nair R, Shariq M, Dhamgaye S, Mukhopadhyay CK, Shaikh S, Prasad R. Non-heat shock responsive roles of HSF1 in Candida albicans are essential under iron deprivation and drug defense. Biochim Biophys Acta Mol Cell Res 2017; 1864(2): 345-54.
[http://dx.doi.org/10.1016/j.bbamcr.2016.11.021] [PMID: 27889440]
Chakravarti A, Camp K, McNabb DS, Pinto I. The Iron-Dependent Regulation of the Candida albicans Oxidative Stress Response by the CCAAT-Binding Factor. PLoS One 2017; 12(1)e0170649
[http://dx.doi.org/10.1371/journal.pone.0170649] [PMID: 28122000]
Skrahina V, Brock M, Hube B, Brunke S. Candida albicans Hap43 Domains Are Required under Iron Starvation but Not Excess. Front Microbiol 2017; 8: 2388.
[http://dx.doi.org/10.3389/fmicb.2017.02388] [PMID: 29250054]
Dong Y, Zhang D, Yu Q, et al. Loss of Ssq1 leads to mitochondrial dysfunction, activation of autophagy and cell cycle arrest due to iron overload triggered by mitochondrial iron-sulfur cluster assembly defects in Candida albicans. Int J Biochem Cell Biol 2017; 85: 44-55.
[http://dx.doi.org/10.1016/j.biocel.2017.01.021] [PMID: 28163187]
Okamoto-Shibayama K, Kikuchi Y, Kokubu E, Sato Y, Ishihara K. Csa2, a member of the Rbt5 protein family, is involved in the utilization of iron from human hemoglobin during Candida albicans hyphal growth. FEMS Yeast Res 2014; 14(4): 674-7.
[http://dx.doi.org/10.1111/1567-1364.12160] [PMID: 24796871]
Zhang D, Dong Y, Yu Q, et al. Function of glutaredoxin 3 (Grx3) in oxidative stress response caused by iron homeostasis disorder in Candida albicans. Future Microbiol 2017; 12: 1397-412.
[http://dx.doi.org/10.2217/fmb-2017-0098] [PMID: 29039220]
Wander K, Shell-Duncan B, Brindle E. Lower incidence of respiratory infections among iron-deficient children in Kilimanjaro, Tanzania. Evol Med Public Health 2017; 2017(1): 109-19.
[http://dx.doi.org/10.1093/emph/eox010] [PMID: 28852503]
Mochon AB, Jin Y, Kayala MA, et al. Serological profiling of a Candida albicans protein microarray reveals permanent host-pathogen interplay and stage-specific responses during candidemia. PLoS Pathog 2010; 6(3)e1000827
[http://dx.doi.org/10.1371/journal.ppat.1000827] [PMID: 20361054]
Xu N, Qian K, Dong Y, et al. Novel role of the Candida albicans ferric reductase gene CFL1 in iron acquisition, oxidative stress tolerance, morphogenesis and virulence. Res Microbiol 2014; 165(3): 252-61.
[http://dx.doi.org/10.1016/j.resmic.2014.03.001] [PMID: 24631590]
Singh RP, Prasad HK, Sinha I, Agarwal N, Natarajan K. Cap2-HAP complex is a critical transcriptional regulator that has dual but contrasting roles in regulation of iron homeostasis in Candida albicans. J Biol Chem 2011; 286(28): 25154-70.
[http://dx.doi.org/10.1074/jbc.M111.233569] [PMID: 21592964]
Brena S, Cabezas-Olcoz J, Moragues MD, et al. Fungicidal monoclonal antibody C7 interferes with iron acquisition in Candida albicans. Antimicrob Agents Chemother 2011; 55(7): 3156-63.
[http://dx.doi.org/10.1128/AAC.00892-10] [PMID: 21518848]
Lu SY. Perception of iron deficiency from oral mucosa alterations that show a high prevalence of Candida infection. J Formos Med Assoc 2016; 115(8): 619-27.
[http://dx.doi.org/10.1016/j.jfma.2016.03.011] [PMID: 27133388]
Gerwien F, Skrahina V, Kasper L, Hube B, Brunke S. Metals in fungal virulence. FEMS Microbiol Rev 2018; 42(1): 1-21.
[http://dx.doi.org/10.1093/femsre/fux050] [PMID: 29069482]
Festa RA, Thiele DJ. Copper: an essential metal in biology. Curr Biol 2011; 21(21): R877-83.
[http://dx.doi.org/10.1016/j.cub.2011.09.040] [PMID: 22075424]
Macomber L, Rensing C, Imlay JA. Intracellular copper does not catalyze the formation of oxidative DNA damage in Escherichia coli. J Bacteriol 2007; 189(5): 1616-26.
[http://dx.doi.org/10.1128/JB.01357-06] [PMID: 17189367]
Andreini C, Bertini I, Cavallaro G, Holliday GL, Thornton JM. Metal ions in biological catalysis: from enzyme databases to general principles. J Biol Inorg Chem 2008; 13(8): 1205-18.
[http://dx.doi.org/10.1007/s00775-008-0404-5] [PMID: 18604568]
Kim BE, Nevitt T, Thiele DJ. Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol 2008; 4(3): 176-85.
[http://dx.doi.org/10.1038/nchembio.72] [PMID: 18277979]
De Feo CJ, Mootien S, Unger VM. Tryptophan scanning analysis of the membrane domain of CTR-copper transporters. J Membr Biol 2010; 234(2): 113-23.
[http://dx.doi.org/10.1007/s00232-010-9239-4] [PMID: 20224886]
Puig S, Lee J, Lau M, Thiele DJ. Biochemical and genetic analyses of yeast and human high affinity copper transporters suggest a conserved mechanism for copper uptake. J Biol Chem 2002; 277(29): 26021-30.
[http://dx.doi.org/10.1074/jbc.M202547200] [PMID: 11983704]
Pena MM, Puig S, Thiele DJ. Characterization of the Saccharomyces cerevisiae high affinity copper transporter Ctr3. J Biol Chem 2000; 275(43): 33244-51.
[http://dx.doi.org/10.1074/jbc.M005392200] [PMID: 10924521]
Rees EM, Lee J, Thiele DJ. Mobilization of intracellular copper stores by the ctr2 vacuolar copper transporter. J Biol Chem 2004; 279(52): 54221-9.
[http://dx.doi.org/10.1074/jbc.M411669200] [PMID: 15494390]
Lin SJ, Pufahl RA, Dancis A, O’Halloran TV, Culotta VC. A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport. J Biol Chem 1997; 272(14): 9215-20.
[http://dx.doi.org/10.1074/jbc.272.14.9215] [PMID: 9083054]
Weissman Z, Berdicevsky I, Cavari BZ, Kornitzer D. The high copper tolerance of Candida albicans is mediated by a P-type ATPase. Proc Natl Acad Sci USA 2000; 97(7): 3520-5.
[http://dx.doi.org/10.1073/pnas.97.7.3520] [PMID: 10737803]
Buchman C, Skroch P, Welch J, Fogel S, Karin M. The CUP2 gene product, regulator of yeast metallothionein expression, is a copper-activated DNA-binding protein. Mol Cell Biol 1989; 9(9): 4091-5.
[http://dx.doi.org/10.1128/MCB.9.9.4091] [PMID: 2674688]
Zhu Z, Labbé S, Peña MM, Thiele DJ. Copper differentially regulates the activity and degradation of yeast Mac1 transcription factor. J Biol Chem 1998; 273(3): 1277-80.
[http://dx.doi.org/10.1074/jbc.273.3.1277] [PMID: 9430656]
Li CX, Gleason JE, Zhang SX, Bruno VM, Cormack BP, Culotta VC. Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase. Proc Natl Acad Sci USA 2015; 112(38): E5336-42.
[http://dx.doi.org/10.1073/pnas.1513447112] [PMID: 26351691]
Casey AL, Adams D, Karpanen TJ, et al. Role of copper in reducing hospital environment contamination. J Hosp Infect 2010; 74(1): 72-7.
[http://dx.doi.org/10.1016/j.jhin.2009.08.018] [PMID: 19931938]
Agertt F, Crippa AC, Lorenzoni PJ, Scola RH, Bruck I. Paola Ld, Silvado CE, Werneck LC. Menkes’ disease: case report. Arq Neuropsiquiatr 2007; 65: 57-160.
Samanovic MI, Ding C, Thiele DJ, Darwin KH. Copper in microbial pathogenesis: meddling with the metal. Cell Host Microbe 2012; 11(2): 106-15.
[http://dx.doi.org/10.1016/j.chom.2012.01.009] [PMID: 22341460]
Liu Y, He X, Liu X, et al. Synthesis of baicalin-copper and baicalin-aluminium complex and its bioactivity Zhongguo Zhongyao Zazhi 2012; 37(9): 1296-302.
[PMID: 22803379]
García-Santamarina S, Thiele DJ. Copper at the Fungal Pathogen-Host Axis. J Biol Chem 2015; 290(31): 18945-53.
[http://dx.doi.org/10.1074/jbc.R115.649129] [PMID: 26055724]
Irene G, Georgios P, Ioannis C, et al. Copper-coated textiles: armor against MDR nosocomial pathogens. Diagn Microbiol Infect Dis 2016; 85(2): 205-9.
[http://dx.doi.org/10.1016/j.diagmicrobio.2016.02.015] [PMID: 27055400]
Zheng S, Chang W, Li C, Lou H. Als1 and Als3 regulate the intracellular uptake of copper ions when Candida albicans biofilms are exposed to metallic copper surfaces. FEMS Yeast Res 2016; 16(3): 1-8.
[http://dx.doi.org/10.1093/femsyr/fow029] [PMID: 27189057]
Diaz JR, Fernández Baldo M, Echeverría G, et al. A substituted sulfonamide and its Co (II), Cu (II), and Zn (II) complexes as potential antifungal agents J Enzyme Inhib Med Chem 2016; 31(sup2): 51-62.
[http://dx.doi.org/10.1080/14756366.2016.1187143] [PMID: 27232977]
Beckford FA, Webb KR. Copper complexes containing thiosemicarbazones derived from 6-nitropiperonal: Antimicrobial and biophysical properties. Spectrochim Acta A Mol Biomol Spectrosc 2017; 183: 158-71.
[http://dx.doi.org/10.1016/j.saa.2017.04.057] [PMID: 28448954]
Chudzik B, Tracz IB, Czernel G, Fiołka MJ, Borsuk G, Gagoś M. Amphotericin B-copper(II) complex as a potential agent with higher antifungal activity against Candida albicans. Eur J Pharm Sci 2013; 49(5): 850-7.
[http://dx.doi.org/10.1016/j.ejps.2013.06.007] [PMID: 23791641]
Besold AN, Gilston BA, Radin JN, et al. The role of calprotectin in withholding zinc and copper from Candida albicans. Infect Immun 2018; 86(2): 79-17.
[PMID: 29133349]
Crawford A, Wilson D. Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens. FEMS Yeast Res 2015; 15(7): 1-11.
[http://dx.doi.org/10.1093/femsyr/fov071] [PMID: 26242402]
Ballo MKS, Rtimi S, Kiwi J, Pulgarin C, Entenza JM, Bizzini A. Fungicidal activity of copper-sputtered flexible surfaces under dark and actinic light against azole-resistant Candida albicans and Candida glabrata. J Photochem Photobiol B 2017; 174: 229-34.
[http://dx.doi.org/10.1016/j.jphotobiol.2017.07.030] [PMID: 28802173]
Gandra RM, Mc Carron P, Fernandes MF, et al. Antifungal Potential of Copper(II), Manganese(II) and Silver(I) 1,10-Phenanthroline Chelates Against Multidrug-Resistant Fungal Species Forming the Candida haemulonii Complex: Impact on the Planktonic and Biofilm Lifestyles. Front Microbiol 2017; 8: 1257.
[http://dx.doi.org/10.3389/fmicb.2017.01257] [PMID: 28744261]
Eide DJ. The molecular biology of metal ion transport in Saccharomyces cerevisiae. Annu Rev Nutr 1998; 18: 441-69.
[http://dx.doi.org/10.1146/annurev.nutr.18.1.441] [PMID: 9706232]
Andreini C, Banci L, Bertini I, Rosato A. Zinc through the three domains of life. J Proteome Res 2006; 5(11): 3173-8.
[http://dx.doi.org/10.1021/pr0603699] [PMID: 17081069]
Andreini C, Bertini I. A bioinformatics view of zinc enzymes. J Inorg Biochem 2012; 111: 150-6.
[http://dx.doi.org/10.1016/j.jinorgbio.2011.11.020] [PMID: 22209023]
McDevitt CA, Ogunniyi AD, Valkov E, et al. A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathog 2011; 7(11)e1002357
[http://dx.doi.org/10.1371/journal.ppat.1002357] [PMID: 22072971]
Jung WH. The Zinc Transport Systems and Their Regulation in Pathogenic Fungi. Mycobiology 2015; 43(3): 179-83.
[http://dx.doi.org/10.5941/MYCO.2015.43.3.179] [PMID: 26539032]
Nobile CJ, Nett JE, Hernday A. D, Homann OR, Deneault JS, Nantel A, Andes D.R, Johnson AD, Mitchell AP. Biofilm ma-trix regulation by Candida albicans Zap1. PLoS Biol 2009; 7: 10-9.
Jensen LT, Ajua-Alemanji M, Culotta VC. The Saccharomyces cerevisiae high affinity phosphate transporter encoded by PHO84 also functions in manganese homeostasis. J Biol Chem 2003; 278(43): 42036-40.
[http://dx.doi.org/10.1074/jbc.M307413200] [PMID: 12923174]
Li L, Kaplan J. The yeast gene MSC2, a member of the cation diffusion facilitator family, affects the cellular distribution of zinc. J Biol Chem 2001; 276(7): 5036-43.
[http://dx.doi.org/10.1074/jbc.M008969200] [PMID: 11058603]
MacDiarmid CW, Gaither LA, Eide D. Zinc transporters that regulate vacuolar zinc storage in Saccharomyces cerevisiae. EMBO J 2000; 19(12): 2845-55.
[http://dx.doi.org/10.1093/emboj/19.12.2845] [PMID: 10856230]
Citiulo F, Jacobsen ID, Miramón P, et al. Candida albicans scavenges host zinc via Pra1 during endothelial invasion. PLoS Pathog 2012; 8(6)e1002777
[http://dx.doi.org/10.1371/journal.ppat.1002777] [PMID: 22761575]
Eide DJ. Zinc transporters and the cellular trafficking of zinc. Biochim Biophys Acta 2006; 1763(7): 711-22.
[http://dx.doi.org/10.1016/j.bbamcr.2006.03.005] [PMID: 16675045]
Lulloff SJ, Hahn BL, Sohnle PG. Fungal susceptibility to zinc deprivation. J Lab Clin Med 2004; 144(4): 208-14.
[http://dx.doi.org/10.1016/j.lab.2004.07.007] [PMID: 15514589]
Polvi EJ, Averette AF, Lee SC, et al. Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis. PLoS Genet 2016; 12(10)e1006350
[http://dx.doi.org/10.1371/journal.pgen.1006350] [PMID: 27695031]
Issi L, Farrer RA, Pastor K, et al. Zinc Cluster Transcription Factors Alter Virulence in Candida albicans. Genetics 2017; 205(2): 559-76.
[http://dx.doi.org/10.1534/genetics.116.195024] [PMID: 27932543]
Böttcher B, Palige K, Jacobsen ID, Hube B, Brunke S. Csr1/Zap1 Maintains Zinc Homeostasis and Influences Virulence in Candida dubliniensis but Is Not Coupled to Morphogenesis. Eukaryot Cell 2015; 14(7): 661-70.
[http://dx.doi.org/10.1128/EC.00078-15] [PMID: 26002718]
McCourt P, Liu HY, Parker JE, et al. Proper Sterol Distribution Is Required for Candida albicans Hyphal Formation and Virulence. G3 (Bethesda) 2016; 6(11): 3455-65.
[http://dx.doi.org/10.1534/g3.116.033969] [PMID: 27587298]
Cazalini EM, Miyakawa W, Teodoro GR, et al. Antimicrobial and anti-biofilm properties of polypropylene meshes coated with metal-containing DLC thin films. J Mater Sci Mater Med 2017; 28(6): 97.
[http://dx.doi.org/10.1007/s10856-017-5910-y] [PMID: 28560581]
Xu Q, Zheng Z, Wang B, Mao H, Yan F. Zinc Ion Coordinated Poly(Ionic Liquid) Antimicrobial Membranes for Wound Healing. ACS Appl Mater Interfaces 2017; 9(17): 14656-64.
[http://dx.doi.org/10.1021/acsami.7b01677] [PMID: 28418650]
Jiao L, Lin F, Cao S, et al. Preparation, characterization, antimicrobial and cytotoxicity studies of copper/zinc- loaded montmorillonite. J Anim Sci Biotechnol 2017; 8: 27.
[http://dx.doi.org/10.1186/s40104-017-0156-6] [PMID: 28331609]
Tebung WA, Omran RP, Fulton DL, Morschhäuser J, Whiteway M. Put3 Positively Regulates Proline Utilization in Candida albicans. MSphere 2017; 2(6): 354-17.
[http://dx.doi.org/10.1128/mSphere.00354-17] [PMID: 29242833]
Malavia D, Lehtovirta-Morley LE, Alamir O, et al. Zinc Limitation Induces a Hyper-Adherent Goliath Phenotype in Candida albicans. Front Microbiol 2017; 8: 2238.
[http://dx.doi.org/10.3389/fmicb.2017.02238] [PMID: 29184547]
Łoboda D, Rowińska-Żyrek M. Zinc binding sites in Pra1, a zincophore from Candida albicans. Dalton Trans 2017; 46(40): 13695-703.
[http://dx.doi.org/10.1039/C7DT01675A] [PMID: 28725901]
O’Hanlon Cohrt KA, Marín L, Kjellerup L, Clausen JD. Novel zinc attenuating compounds as potent broad spectrum antifungal agents with in vitro and in vivo efficacy. Antimicrob Agents Chemother 2018; 4: 02024-17.
Liu S, Hou Y, Liu W, Lu C, Wang W, Sun S. Components of the calcium-calcineurin signaling pathway in fungal cells and their potential as antifungal targets. Eukaryot Cell 2015; 14(4): 324-34.
[http://dx.doi.org/10.1128/EC.00271-14] [PMID: 25636321]
de Castro PA, Chiaratto J, Winkelströter LK, et al. The involvement of the Mid1/Cch1/Yvc1 calcium channels in Aspergillus fumigatus virulence. PLoS One 2014; 9(8)e103957
[http://dx.doi.org/10.1371/journal.pone.0103957] [PMID: 25083783]
Harren K, Tudzynski B. Cch1 and Mid1 are functionally required for vegetative growth under low-calcium conditions in the phytopathogenic ascomycete Botrytis cinerea. Eukaryot Cell 2013; 12(5): 712-24.
[http://dx.doi.org/10.1128/EC.00338-12] [PMID: 23475703]
Zhang J, Silao FG, Bigol UG, et al. Calcineurin is required for pseudohyphal growth, virulence, and drug resistance in Candida lusitaniae. PLoS One 2012; 7(8)e44192
[http://dx.doi.org/10.1371/journal.pone.0044192] [PMID: 22952924]
Del Aguila EM, Silva JT, Paschoalin VM. Expression of the yeast calcineurin subunits CNA1 and CNA2 during growth and hyper-osmotic stress. FEMS Microbiol Lett 2003; 221(2): 197-202.
[http://dx.doi.org/10.1016/S0378-1097(03)00181-2] [PMID: 12725927]
Rusnak F, Mertz P. Calcineurin: form and function. Physiol Rev 2000; 80(4): 1483-521.
[http://dx.doi.org/10.1152/physrev.2000.80.4.1483] [PMID: 11015619]
Watanabe Y, Perrino BA, Chang BH, Soderling TR. Identification in the calcineurin A subunit of the domain that binds the regulatory B subunit. J Biol Chem 1995; 270(1): 456-60.
[http://dx.doi.org/10.1074/jbc.270.1.456] [PMID: 7814411]
Cyert MS. Genetic analysis of calmodulin and its targets in Saccharomyces cerevisiae. Annu Rev Genet 2001; 35: 647-72.
[http://dx.doi.org/10.1146/annurev.genet.35.102401.091302] [PMID: 11700296]
Zhao Y, Du J, Xiong B, Xu H, Jiang L. ESCRT components regulate the expression of the ER/Golgi calcium pump gene PMR1 through the Rim101/Nrg1 pathway in budding yeast. J Mol Cell Biol 2013; 5(5): 336-44.
[http://dx.doi.org/10.1093/jmcb/mjt025] [PMID: 23933635]
Cunningham KW, Fink GR. Calcineurin-dependent growth control in Saccharomyces cerevisiae mutants lacking PMC1, a homolog of plasma membrane Ca2+ ATPases. J Cell Biol 1994; 124(3): 351-63.
[http://dx.doi.org/10.1083/jcb.124.3.351] [PMID: 7507493]
Spötl L, Möst J, Dierich MP. Ca ions stabilize the binding of complement factor iC3b to the pseudohyphal form of Candida albicans. Infect Immun 1994; 62(3): 1125-7.
[http://dx.doi.org/10.1128/IAI.62.3.1125-1127.1994] [PMID: 8112846]
Yang M, Brand A, Srikantha T, Daniels KJ, Soll DR. Gow, N.A. Fig1 facilitates calcium influx and localizes to mem-branes destined to undergo fusion during mating in Candida albicans. Eukaryot Cell 2011; 201(10): 435-44.
Shi W, Chen Z, Chen X, Cao L, Liu P, Sun S. The combination of minocycline and fluconazole causes synergistic growth inhibition against Candida albicans: an in vitro interaction of antifungal and antibacterial agents. FEMS Yeast Res 2010; 10(7): 885-93.
[http://dx.doi.org/10.1111/j.1567-1364.2010.00664.x] [PMID: 20707818]
Tisi R, Rigamonti M, Groppi S, Belottiv F. Calcium homeosta-sis and signaling in fungi and their relevance for pathogenicity of yeasts and filamentous fungi. AIMS Mol Sci 2016; 34: 505-49.
Wang Y, Wang J, Cheng J, Xu D, Jiang L. Genetic interactions between the Golgi Ca2+/H+ exchanger Gdt1 and the plasma membrane calcium channel Cch1/Mid1 in the regulation of calcium homeostasis, stress response and virulence in Candida albicans. FEMS Yeast Res 2015; 15(7)fov069
[http://dx.doi.org/10.1093/femsyr/fov069] [PMID: 26208803]
Liu S, Yue L, Gu W, Li X, Zhang L, Sun S. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans. PLoS One 2016; 11(3)e0150859
[http://dx.doi.org/10.1371/journal.pone.0150859] [PMID: 26986478]
Jia W. hang H, Li C, Li G, Liu X, Wei J. The calcineruin inhib-itor cyclosporine a synergistically enhances the susceptibility of Candida albicans biofilms to fluconazole by multiple mechanisms. BMC Microbiol 2016; 16: 113.
[http://dx.doi.org/10.1186/s12866-016-0728-1] [PMID: 27316338]
Tian H, Qu S, Wang Y, et al. Calcium and oxidative stress mediate perillaldehyde-induced apoptosis in Candida albicans. Appl Microbiol Biotechnol 2017; 101(8): 3335-45.
[http://dx.doi.org/10.1007/s00253-017-8146-3] [PMID: 28224196]
Li J, Zhang B, Ma T, et al. Role of the Inositol Polyphosphate Multikinase Ipk2 in Regulation of Hyphal Development, Calcium Signaling and Secretion in Candida albicans. Mycopathologia 2017; 182(7-8): 609-23.
[http://dx.doi.org/10.1007/s11046-017-0138-4] [PMID: 28501915]
Jia C, Zhang K, Zhang D, et al. Effects of Disruption of PMC1 in the tfp1∆/∆ Mutant on Calcium Homeostasis, Oxidative and Osmotic Stress Resistance in Candida albicans. Mycopathologia 2018; 183(2): 315-27.
[http://dx.doi.org/10.1007/s11046-017-0216-7] [PMID: 29086141]
Chakraborti S, Chakraborti T, Mandal M, Mandal A, Das S, Ghosh S. Protective role of magnesium in cardiovascular diseases: a review. Mol Cell Biochem 2002; 238(1-2): 163-79.
[http://dx.doi.org/10.1023/A:1019998702946] [PMID: 12349904]
Anastassopoulou J, Theophanides T. Magnesium-DNA interactions and the possible relation of magnesium to carcinogenesis. Irradiation and free radicals. Crit Rev Oncol Hematol 2002; 42(1): 79-91.
[http://dx.doi.org/10.1016/S1040-8428(02)00006-9] [PMID: 11923070]
Moomaw AS, Maguire ME. The unique nature of mg2+ channels. Physiology (Bethesda) 2008; 23: 275-85.
[http://dx.doi.org/10.1152/physiol.00019.2008] [PMID: 18927203]
Schindl R, Weghuber J, Romanin C, Schweyen RJ. Mrs2p forms a high conductance Mg2+ selective channel in mitochondria. Biophys J 2007; 93(11): 3872-83.
[http://dx.doi.org/10.1529/biophysj.107.112318] [PMID: 17827224]
Graschopf A, Stadler JA, Hoellerer MK, et al. The yeast plasma membrane protein Alr1 controls Mg2+ homeostasis and is subject to Mg2+-dependent control of its synthesis and degradation. J Biol Chem 2001; 276(19): 16216-22.
[http://dx.doi.org/10.1074/jbc.M101504200] [PMID: 11279208]
Wachek M, Aichinger MC, Stadler JA, Schweyen RJ, Graschopf A. Oligomerization of the Mg2+-transport proteins Alr1p and Alr2p in yeast plasma membrane. FEBS J 2006; 273(18): 4236-49.
[http://dx.doi.org/10.1111/j.1742-4658.2006.05424.x] [PMID: 16903865]
Johansson MJ, Jacobson A. Nonsense-mediated mRNA decay maintains translational fidelity by limiting magnesium uptake. Genes Dev 2010; 24(14): 1491-5.
[http://dx.doi.org/10.1101/gad.1930710] [PMID: 20634315]
Walker GM, Sullivan PA, Shepherd MG. Magnesium and the regulation of germ-tube formation in Candida albicans. J Gen Microbiol 1984; 130(8): 1941-5.
[PMID: 6432954]
MacDiarmid CW, Gardner RC. Overexpression of the Saccha-romyces cerevisiae magnesium transport system confers re-sistance to aluminum ion. J. Biol. Chem. 1998; 273: 1727-32.da Costa, B.M.; Cornish, K.; Keasling, J.D. Manipulation of intracellular magnesium levels in Saccharomyces cerevisiae with deletion of magnesium transporters. Appl Microbiol Biotechnol 2007; 77: 411-25.
Lee JM, Gardner RC. Residues of the yeast ALR1 protein that are critical for magnesium uptake. Curr Genet 2006; 49(1): 7-20.
[http://dx.doi.org/10.1007/s00294-005-0037-y] [PMID: 16328501]
Bleackley MR, Hayes BM, Parisi K, et al. Bovine pancreatic trypsin inhibitor is a new antifungal peptide that inhibits cellular magnesium uptake. Mol Microbiol 2014; 92(6): 1188-97.
[http://dx.doi.org/10.1111/mmi.12621] [PMID: 24750237]
Remus BS, Goldgur Y, Shuman S. Structural basis for the GTP specificity of the RNA kinase domain of fungal tRNA ligase. Nucleic Acids Res 2017; 45(22): 12945-53.
[http://dx.doi.org/10.1093/nar/gkx1159] [PMID: 29165709]
Greenwood NN, Earnshaw A. Chemistry of the Elements. 2nd ed. Oxford, UK: Butterworth-Heinemann 1997.
Conrad M, Schothorst J, Kankipati HN, Van Zeebroeck G, Rubio-Texeira M, Thevelein JM. Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae. FEMS Microbiol Rev 2014; 38(2): 254-99.
[http://dx.doi.org/10.1111/1574-6976.12065] [PMID: 24483210]
Teunissen JHM, Crooijmans ME, Teunisse PPP, van Heusden GPH. Lack of 14-3-3 proteins in Saccharomyces cerevisiae results in cell-to-cell heterogeneity in the expression of Pho4-regulated genes SPL2 and PHO84. BMC Genomics 2017; 18(1): 701.
[http://dx.doi.org/10.1186/s12864-017-4105-8] [PMID: 28877665]
Vicent I, Navarro A, Mulet JM, Sharma S, Serrano R. Uptake of inorganic phosphate is a limiting factor for Saccharomyces cerevisiae during growth at low temperatures. FEMS Yeast Res 2015; 15(3)fov008
[http://dx.doi.org/10.1093/femsyr/fov008] [PMID: 25725023]
Kaffman A. erskowitz I, Tjian R, O’Shea EK. Phosphoryla-tion of the transcription factor PHO4 by a cyclin-CDK com-plex, PHO80-PHO85. Science 1994; 263: 1153-6.
[http://dx.doi.org/10.1126/science.8108735] [PMID: 8108735]
O’Neill EM, Kaffman A, Jolly ER, O’Shea EK. Regulation of PHO4 nuclear localization by the PHO80-PHO85 cyclin-CDK complex. Science 1996; 271(5246): 209-12.
[http://dx.doi.org/10.1126/science.271.5246.209] [PMID: 8539622]
Ikeh MA, Kastora SL, Day AM, et al. Pho4 mediates phosphate acquisition in Candida albicans and is vital for stress resistance and metal homeostasis. Mol Biol Cell 2016; 27(17): 2784-801.
[http://dx.doi.org/10.1091/mbc.e16-05-0266] [PMID: 27385340]
Flick JS, Thorner J. An essential function of a phosphoinositide-specific phospholipase C is relieved by inhibition of a cyclin-dependent protein kinase in the yeast Saccharomyces cerevisiae. Genetics 1998; 148(1): 33-47.
[PMID: 9475719]
Anemaet IG, van Heusden GP. Transcriptional response of Saccharomyces cerevisiae to potassium starvation. BMC Genomics 2014; 15: 1040.
[http://dx.doi.org/10.1186/1471-2164-15-1040] [PMID: 25432801]
Hürlimann HC, Stadler-Waibel M, Werner TP, Freimoser FM. Pho91 Is a vacuolar phosphate transporter that regulates phosphate and polyphosphate metabolism in Saccharomyces cerevisiae. Mol Biol Cell 2007; 18(11): 4438-45.
[http://dx.doi.org/10.1091/mbc.e07-05-0457] [PMID: 17804816]
Pérez-Sampietro M, Serra-Cardona A, Canadell D, Casas C, Ariño J, Herrero E. The yeast Aft2 transcription factor determines selenite toxicity by controlling the low affinity phosphate transport system. Sci Rep 2016; 6: 32836.
[http://dx.doi.org/10.1038/srep32836] [PMID: 27618952]
Liu NN, Flanagan PR, Zeng J, et al. Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition. Proc Natl Acad Sci USA 2017; 114(24): 6346-51.
[http://dx.doi.org/10.1073/pnas.1617799114] [PMID: 28566496]
Powell B, Graham LA, Stevens TH. Molecular characterization of the yeast vacuolar H+-ATPase proton pore. J Biol Chem 2000; 275(31): 23654-60.
[http://dx.doi.org/10.1074/jbc.M004440200] [PMID: 10825180]
Elicharová H, Hušeková B, Sychrová H. Three Candida albicans potassium uptake systems differ in their ability to provide Saccharomyces cerevisiae trk1trk2 mutants with necessary potassium. FEMS Yeast Res 2016; 16(4): 34-9.
[http://dx.doi.org/10.1093/femsyr/fow039] [PMID: 27189364]
Kahm M, Navarrete C, Llopis-Torregrosa V, et al. Potassium starvation in yeast: mechanisms of homeostasis revealed by mathematical modeling. PLOS Comput Biol 2012; 8(6)e1002548
[http://dx.doi.org/10.1371/journal.pcbi.1002548] [PMID: 22737060]
Vylkova S, Jang WS, Li W, Nayyar N, Edgerton M. Histatin 5 initiates osmotic stress response in Candida albicans via activation of the Hog1 mitogen-activated protein kinase pathway. Eukaryot Cell 2007; 6(10): 1876-88.
[http://dx.doi.org/10.1128/EC.00039-07] [PMID: 17715369]
Peña A, Sánchez NS, Calahorra M. Effects of chitosan on Candida albicans: conditions for its antifungal activity. BioMed Res Int 2013. 2013527549
[http://dx.doi.org/10.1155/2013/527549] [PMID: 23844364]
Llopis-Torregrosa V, Hušeková B, Sychrová H. Potassium Uptake Mediated by Trk1 Is Crucial for Candida glabrata Growth and Fitness. PLoS One 2016; 11(4)e0153374
[http://dx.doi.org/10.1371/journal.pone.0153374] [PMID: 27058598]
Yun J, Lee DG. Role of potassium channels in chlorogenic acid-induced apoptotic volume decrease and cell cycle arrest in Candida albicans. Biochim Biophys Acta, Gen Subj 2017; 1861(3): 585-92.
[http://dx.doi.org/10.1016/j.bbagen.2016.12.026] [PMID: 28040564]
Lee W, Lee DG. Potential role of potassium and chloride channels in regulation of silymarin-induced apoptosis in Candida albicans. IUBMB Life 2018; 70(3): 197-206.
[http://dx.doi.org/10.1002/iub.1716] [PMID: 29356280]
Lee W, Lee DG. Reactive oxygen species modulate itraconazole-induced apoptosis via mitochondrial disruption in Candida albicans. Free Radic Res 2018; 52(1): 39-50.
[http://dx.doi.org/10.1080/10715762.2017.1407412] [PMID: 29157011]
Reddi AR, Jensen LT, Culotta VC. Manganese homeostasis in Saccharomyces cerevisiae. Chem Rev 2009; 109(10): 4722-32.
[http://dx.doi.org/10.1021/cr900031u] [PMID: 19705825]
Liang Q, Zhou B. Copper and manganese induce yeast apoptosis via different pathways. Mol Biol Cell 2007; 18(12): 4741-9.
[http://dx.doi.org/10.1091/mbc.e07-05-0431] [PMID: 17881727]
Portnoy ME, Liu XF, Culotta VC. Saccharomyces cerevisiae expresses three functionally distinct homologues of the nramp family of metal transporters. Mol Cell Biol 2000; 20(21): 7893-902.
[http://dx.doi.org/10.1128/MCB.20.21.7893-7902.2000] [PMID: 11027260]
Cohen A, Nelson H, Nelson N. The family of SMF metal ion transporters in yeast cells. J Biol Chem 2000; 275(43): 33388-94.
[http://dx.doi.org/10.1074/jbc.M004611200] [PMID: 10930410]
Dürr G, Strayle J, Plemper R, et al. The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation. Mol Biol Cell 1998; 9(5): 1149-62.
[http://dx.doi.org/10.1091/mbc.9.5.1149] [PMID: 9571246]
DOILamarre C. LeMay JD. Deslaurier N, Bourbonnais Y. Candida albicans expresses an unusual cytoplasmic manga-nese-containing superoxide dismutase (SOD3 gene product) upon the entry and during the stationary phase. J Biol Chem 2001; 276: 43784-91.
[http://dx.doi.org/10.1074/jbc.M108095200] [PMID: 11562375]
Hwang CS, Baek YU, Yim HS, Kang SO. Protective roles of mitochondrial manganese-containing superoxide dismutase against various stresses in Candida albicans. Yeast 2003; 20(11): 929-41.
[http://dx.doi.org/10.1002/yea.1004] [PMID: 12898709]
Ryazanova L, Zvonarev A, Rusakova T, Dmitriev V, Kulakovskaya T. Manganese tolerance in yeasts involves polyphosphate, magnesium, and vacuolar alterations. Folia Microbiol (Praha) 2016; 61(4): 311-7.
[http://dx.doi.org/10.1007/s12223-015-0440-9] [PMID: 26646947]

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Year: 2020
Published on: 07 September, 2020
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DOI: 10.2174/1570163816666190227231437
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