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Cited by 37Fungal Infections and StudiesAntifungal resistance and susceptibilityDrug Transport and Resistance Mechanisms

An Atypical ABC Transporter Is Involved in Antifungal Resistance and Host Interactions in the Pathogenic Fungus Cryptococcus neoformans

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Winski, Christopher J., Qian, Yuanyuan, Mobashery, Shahriar, Santiago-Tirado, Felipe H.·2022·mBio
DOI 10.1128/mbio.01539-22PMC PMC9426558

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Abstract

Conserved across all kingdoms of life, ABC transporters comprise one of the largest protein families. They are associated with multidrug resistance, affecting aspects such as resistance to antimicrobials or anti-cancer drugs.

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  • Heteroresistant subpopulations may exist at low frequencies or exhibit resistance only under specific conditions, such as prolonged exposure to antifungal agents or within certain host environments.

    “This limitation arises because heteroresistant subpopulations may exist at low frequencies or exhibit resistance only under specific conditions, such as prolonged exposure to antifungal agents or within certain host environments [153,165,167,168].”

    From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [168]

    The Introduction (page unavailable) identifies heteroresistance as a reported fluconazole-resistance mechanism in C. neoformans. It does not say that resistant subpopulations occur at low frequencies or become resistant only after prolonged antifungal exposure or in particular host environments. (LLM, conf=0.78)

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References 62 · Cited by 37

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  1. [1]Higgins CF. 2001. ABC transporters: physiology, structure and mechanism–an overview. Res Microbiol 152: 205– 210. doi: 10.1016/s0923-2508(01)01193-7. 11421269 · DOI
  2. [2]Jungwirth H, Kuchler K. 2006. Yeast ABC transporters– a tale of sex, stress, drugs and aging. FEBS Lett 580: 1131– 1138. doi: 10.1016/j.febslet.2005.12.050. 16406363 · DOI
  3. [3]Holland IB, Cole SPC, Kuchler K, Higgins CF. 2003. ABC Proteins from bacteria to man. Academic Press, Amsterdam.
  4. [4]Khunweeraphong N, Kuchler K. 2021. Multidrug resistance in mammals and fungi-from MDR to PDR: a rocky road from atomic structures to transport mechanisms. Int J Mol Sci 22: 4806. doi: 10.3390/ijms22094806. 33946618 PMC8124828 · DOI
  5. [5]Lamping E, Baret PV, Holmes AR, Monk BC, Goffeau A, Cannon RD. 2010. Fungal PDR transporters: phylogeny, topology, motifs and function. Fungal Genet Biol 47: 127– 142. doi: 10.1016/j.fgb.2009.10.007. 19857594 PMC2814995 · DOI
  6. [7]Niimi M, Tanabe K, Wada S, Yamazaki A, Uehara Y, Niimi K, Lamping E, Holmes AR, Monk BC, Cannon RD. 2005. ABC transporters of pathogenic fungi: recent advances in functional analyses. Nihon Ishinkin Gakkai Zasshi 46: 249– 260. doi: 10.3314/jjmm.46.249. 16282967 · DOI
  7. [8]Kovalchuk A, Driessen AJ. 2010. Phylogenetic analysis of fungal ABC transporters. BMC Genomics 11: 177. doi: 10.1186/1471-2164-11-177. 20233411 PMC2848647 · DOI
  8. [9]May RC, Stone NR, Wiesner DL, Bicanic T, Nielsen K. 2016. Cryptococcus: from environmental saprophyte to global pathogen. Nat Rev Microbiol 14: 106– 117. doi: 10.1038/nrmicro.2015.6. 26685750 PMC5019959 · DOI · Paper page
  9. [10]Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, Denning DW, Loyse A, Boulware DR. 2017. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis 17: 873– 881. doi: 10.1016/S1473-3099(17)30243-8. 28483415 PMC5818156 · DOI · Paper page
  10. [11]Coelho C, Casadevall A. 2016. Cryptococcal therapies and drug targets: the old, the new and the promising. Cell Microbiol 18: 792– 799. doi: 10.1111/cmi.12590. 26990050 PMC5536168 · DOI
  11. [12]Zhang J, Li L, Lv Q, Yan L, Wang Y, Jiang Y. 2019. The fungal CYP51s: their functions, structures, related drug resistance, and inhibitors. Front Microbiol 10: 691. doi: 10.3389/fmicb.2019.00691. 31068906 PMC6491756 · DOI
  12. [13]Atim PB, Meya DM, Gerlach ES, Muhanguzi D, Male A, Kanamwanji B, Nielsen K. 2022. Lack of association between fluconazole susceptibility and ERG11 nucleotide polymorphisms in Cryptococcus neoformans clinical isolates from Uganda. JoF 8: 508. doi: 10.3390/jof8050508. 35628763 PMC9145384 · DOI
  13. [14]Hope W, Stone NRH, Johnson A, McEntee L, Farrington N, Santoro-Castelazo A, Liu X, Lucaci A, Hughes M, Oliver JD, Giamberardino C, Mfinanga S, Harrison TS, Perfect JR, Bicanic T. 2019. Fluconazole monotherapy is a suboptimal option for initial treatment of cryptococcal meningitis because of emergence of resistance. mBio 10: e02575-19. doi: 10.1128/mBio.02575-19. 31796539 PMC6890991 · DOI · Paper page
  14. [15]Moreira IMB, Cortez ACA, de Souza ES, Pinheiro SB, de Souza Oliveira JG, Sadahiro A, Cruz KS, Matsuura ABJ, Melhem MSC, Frickmann H, de Souza JVB. 2022. Investigation of fluconazole heteroresistance in clinical and environmental isolates of Cryptococcus neoformans complex and Cryptococcus gattii complex in the state of Amazonas. Brazil Med Mycol 60: myac005. doi: 10.1093/mmy/myac005. 35084497 · DOI · Paper page
  15. [16]Yang C, Bian Z, Blechert O, Deng F, Chen H, Li Y, Yang Y, Chen M, Zhan P. 2021. High prevalence of HIV-related Cryptococcosis and increased resistance to fluconazole of the Cryptococcus neoformans complex in Jiangxi Province, South Central China. Front Cell Infect Microbiol 11: 723251. doi: 10.3389/fcimb.2021.723251. 34790585 PMC8592285 · DOI
  16. [17]Sionov E, Chang YC, Garraffo HM, Dolan MA, Ghannoum MA, Kwon-Chung KJ. 2012. Identification of a Cryptococcus neoformans cytochrome P450 lanosterol 14alpha-demethylase (Erg11) residue critical for differential susceptibility between fluconazole/voriconazole and itraconazole/posaconazole. Antimicrob Agents Chemother 56: 1162– 1169. doi: 10.1128/AAC.05502-11. 22155829 PMC3294891 · DOI
  17. [19]Bennett RJ, Forche A, Berman J. 2014. Rapid mechanisms for generating genome diversity: whole ploidy shifts, aneuploidy, and loss of heterozygosity. Cold Spring Harb Perspect Med 4: a019604. doi: 10.1101/cshperspect.a019604. 25081629 PMC4200206 · DOI · Paper page
  18. [20]Stone NR, Rhodes J, Fisher MC, Mfinanga S, Kivuyo S, Rugemalila J, Segal ES, Needleman L, Molloy SF, Kwon-Chung J, Harrison TS, Hope W, Berman J, Bicanic T. 2019. Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis. J Clin Invest 129: 999– 1014. doi: 10.1172/JCI124516. 30688656 PMC6391087 · DOI · Paper page
  19. [21]Holmes AR, Cardno TS, Strouse JJ, Ivnitski-Steele I, Keniya MV, Lackovic K, Monk BC, Sklar LA, Cannon RD. 2016. Targeting efflux pumps to overcome antifungal drug resistance. Future Med Chem 8: 1485– 1501. doi: 10.4155/fmc-2016-0050. 27463566 PMC5827819 · DOI · Paper page
  20. [22]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. doi: 10.1046/j.1365-2958.2003.03281.x. 12519188 · DOI · Paper page
  21. [23]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. doi: 10.1128/IAI.74.2.1352-1359.2006. 16428784 PMC1360305 · DOI
  22. [24]Chang M, Sionov E, Khanal Lamichhane A, Kwon-Chung KJ, Chang YC. 2018. Roles of three Cryptococcus neoformans and Cryptococcus gattii efflux pump-coding genes in response to drug treatment. Antimicrob Agents Chemother 62: e01751-17. doi: 10.1128/AAC.01751-17. 29378705 PMC5913978 · DOI
  23. [25]Ko YJ, Yu YM, Kim GB, Lee GW, Maeng PJ, Kim S, Floyd A, Heitman J, Bahn YS. 2009. Remodeling of global transcription patterns of Cryptococcus neoformans genes mediated by the stress-activated HOG signaling pathways. Eukaryot Cell 8: 1197– 1217. doi: 10.1128/EC.00120-09. 19542307 PMC2725552 · DOI
  24. [26]Santiago-Tirado FH, Peng T, Yang M, Hang HC, Doering TL. 2015. A Single protein S-acyl transferase acts through diverse substrates to determine cryptococcal morphology, stress tolerance, and pathogenic outcome. PLoS Pathog 11: e1004908. doi: 10.1371/journal.ppat.1004908. 25970403 PMC4430228 · DOI
  25. [27]Inglis DO, Skrzypek MS, Liaw E, Moktali V, Sherlock G, Stajich JE. 2014. Literature-based gene curation and proposed genetic nomenclature for cryptococcus. Eukaryot Cell 13: 878– 883. doi: 10.1128/EC.00083-14. 24813190 PMC4135733 · DOI
  26. [28]Velamakanni S, Wei SL, Janvilisri T, van Veen HW. 2007. ABCG transporters: structure, substrate specificities and physiological roles: a brief overview. J Bioenerg Biomembr 39: 465– 471. doi: 10.1007/s10863-007-9122-x. 17990087 · DOI
  27. [29]Neumann S, Hartmann H, Martin-Galiano AJ, Fuchs A, Frishman D. 2012. Camps 2.0: exploring the sequence and structure space of prokaryotic, eukaryotic, and viral membrane proteins. Proteins 80: 839– 857. doi: 10.1002/prot.23242. 22213543 · DOI
  28. [30]Oliveira FFM, Paes HC, Peconick LDF, Fonseca FL, Marina CLF, Bocca AL, Homem-de-Mello M, Rodrigues ML, Albuquerque P, Nicola AM, Alspaugh JA, Felipe MSS, Fernandes L. 2020. Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans. Fungal Genet Biol 140: 103368. doi: 10.1016/j.fgb.2020.103368. 32201128 PMC7293587 · DOI
  29. [31]Brown HE, Telzrow CL, Saelens JW, Fernandes L, Alspaugh JA. 2020. Sterol-response pathways mediate alkaline survival in diverse fungi. mBio 11: e00719-20. doi: 10.1128/mBio.00719-20. 32546619 PMC7298709 · DOI
  30. [32]Kolaczkowski M, van der Rest M, Cybularz-Kolaczkowska A, Soumillion JP, Konings WN, Goffeau A. 1996. Anticancer drugs, ionophoric peptides, and steroids as substrates of the yeast multidrug transporter Pdr5p. J Biol Chem 271: 31543– 31548. doi: 10.1074/jbc.271.49.31543. 8940170 · DOI
  31. [33]Ivnitski-Steele I, Holmes AR, Lamping E, Monk BC, Cannon RD, Sklar LA. 2009. Identification of Nile red as a fluorescent substrate of the Candida albicans ATP-binding cassette transporters Cdr1p and Cdr2p and the major facilitator superfamily transporter Mdr1p. Anal Biochem 394: 87– 91. doi: 10.1016/j.ab.2009.07.001. 19577533 PMC2739806 · DOI
  32. [34]Benhamou RI, Bibi M, Steinbuch KB, Engel H, Levin M, Roichman Y, Berman J, Fridman M. 2017. Real-time imaging of the azole class of antifungal drugs in live candida cells. ACS Chem Biol 12: 1769– 1777. doi: 10.1021/acschembio.7b00339. 28472585 PMC7030953 · DOI · Paper page
  33. [35]Paul S, Kannan I, Mohanram K. 2019. Extensive ERG11 mutations associated with fluconazole-resistant Candida albicans isolated from HIV-infected patients. Curr Med Mycol 5: 1– 6. doi: 10.18502/cmm.5.3.1739. PMC6910709 31850389 · DOI
  34. [36]Altamirano S, Simmons C, Kozubowski L. 2018. Colony and single cell level analysis of the heterogeneous response of cryptococcus neoformans to fluconazole. Front Cell Infect Microbiol 8: 203. doi: 10.3389/fcimb.2018.00203. 29971221 PMC6018158 · DOI · Paper page
  35. [37]Godinho CP, Prata CS, Pinto SN, Cardoso C, Bandarra NM, Fernandes F, Sa-Correia I. 2018. Pdr18 is involved in yeast response to acetic acid stress counteracting the decrease of plasma membrane ergosterol content and order. Sci Rep 8: 7860. doi: 10.1038/s41598-018-26128-7. 29777118 PMC5959924 · DOI
  36. [38]Godinho CP, Costa R, Sa-Correia I. 2021. The ABC transporter Pdr18 is required for yeast thermotolerance due to its role in ergosterol transport and plasma membrane properties. Environ Microbiol 23: 69– 80. doi: 10.1111/1462-2920.15253. 32985771 PMC7891575 · DOI
  37. [39]Lamping E, Monk BC, Niimi K, Holmes AR, Tsao S, Tanabe K, Niimi M, Uehara Y, Cannon RD. 2007. Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryot Cell 6: 1150– 1165. doi: 10.1128/EC.00091-07. 17513564 PMC1951111 · DOI
  38. [40]Madani G, Lamping E, Lee HJ, Niimi M, Mitra AK, Cannon RD. 2021. Small-scale plasma membrane preparation for the analysis of Candida albicans Cdr1-mGFPHis. J Vis Exp 172. 34180894
  39. [41]Gaylord EA, Choy HL, Doering TL. 2020. Dangerous liaisons: interactions of Cryptococcus neoformans with host phagocytes. Pathogens 9: 891. doi: 10.3390/pathogens9110891. PMC7692806 33121050 · DOI
  40. [42]Zaragoza O, Rodrigues ML, De Jesus M, Frases S, Dadachova E, Casadevall A. 2009. The capsule of the fungal pathogen Cryptococcus neoformans. Adv Appl Microbiol 68: 133– 216. doi: 10.1016/S0065-2164(09)01204-0. 19426855 PMC2739887 · DOI
  41. [43]Denham ST, Verma S, Reynolds RC, Worne CL, Daugherty JM, Lane TE, Brown JCS. 2018. Regulated release of cryptococcal polysaccharide drives virulence and suppresses immune cell infiltration into the central nervous system. Infect Immun 86: e00662-17. doi: 10.1128/IAI.00662-17. 29203547 PMC5820953 · DOI
  42. [44]Yoneda A, Doering TL. 2008. Regulation of Cryptococcus neoformans capsule size is mediated at the polymer level. Eukaryot Cell 7: 546– 549. doi: 10.1128/EC.00437-07. 18156288 PMC2268517 · DOI
  43. [45]Martinez LR, Casadevall A. 2015. Biofilm formation by Cryptococcus neoformans. Microbiol Spectr 3. doi: 10.1128/microbiolspec.MB-0006-2014. 26185073 · DOI
  44. [46]Lee HH, Del Pozzo J, Salamanca SA, Hernandez H, Martinez LR. 2019. Reduced phagocytosis and killing of Cryptococcus neoformans biofilm-derived cells by J774.16 macrophages is associated with fungal capsular production and surface modification. Fungal Genet Biol 132: 103258. doi: 10.1016/j.fgb.2019.103258. 31356873 PMC6905497 · DOI
  45. [47]Ravi S, Pierce C, Witt C, Wormley FL, Jr. 2009. Biofilm formation by Cryptococcus neoformans under distinct environmental conditions. Mycopathologia 167: 307– 314. doi: 10.1007/s11046-008-9180-6. 19130292 PMC4278410 · DOI
  46. [49]Baumann NA, Sullivan DP, Ohvo-Rekila H, Simonot C, Pottekat A, Klaassen Z, Beh CT, Menon AK. 2005. Transport of newly synthesized sterol to the sterol-enriched plasma membrane occurs via nonvesicular equilibration. Biochemistry 44: 5816– 5826. doi: 10.1021/bi048296z. 15823040 · DOI
  47. [50]Kerr ID, Hutchison E, Gerard L, Aleidi SM, Gelissen IC. 2021. Mammalian ABCG-transporters, sterols and lipids: to bind perchance to transport? Biochim Biophys Acta Mol Cell Biol Lipids 1866: 158860. doi: 10.1016/j.bbalip.2020.158860. 33309976 · DOI
  48. [51]Orner EP, Zhang P, Jo MC, Bhattacharya S, Qin L, Fries BC. 2019. High-throughput yeast aging analysis for Cryptococcus (HYAAC) microfluidic device streamlines aging studies in Cryptococcus neoformans. Commun Biol 2: 256. doi: 10.1038/s42003-019-0504-5. 31312725 PMC6620289 · DOI
  49. [52]Kumar P, Heiss C, Santiago-Tirado FH, Black I, Azadi P, Doering TL. 2014. Pbx proteins in Cryptococcus neoformans cell wall remodeling and capsule assembly. Eukaryot Cell 13: 560– 571. doi: 10.1128/EC.00290-13. 24585882 PMC4060484 · DOI
  50. [53]Reese AJ, Doering TL. 2003. Cell wall alpha-1,3-glucan is required to anchor the Cryptococcus neoformans capsule. Mol Microbiol 50: 1401– 1409. doi: 10.1046/j.1365-2958.2003.03780.x. 14622425 · DOI · Paper page
  51. [54]Santiago-Tirado FH, Doering TL. 2017. False friends: phagocytes as Trojan horses in microbial brain infections. PLoS Pathog 13: e1006680. doi: 10.1371/journal.ppat.1006680. 29240825 PMC5730104 · DOI
  52. [55]Liu OW, Chun CD, Chow ED, Chen C, Madhani HD, Noble SM. 2008. Systematic genetic analysis of virulence in the human fungal pathogen Cryptococcus neoformans. Cell 135: 174– 188. doi: 10.1016/j.cell.2008.07.046. 18854164 PMC2628477 · DOI · Paper page
  53. [56]Fu J, Hettler E, Wickes BL. 2006. Split marker transformation increases homologous integration frequency in Cryptococcus neoformans. Fungal Genet Biol 43: 200– 212. doi: 10.1016/j.fgb.2005.09.007. 16497523 · DOI
  54. [58]Franzot SP, Casadevall A. 1997. Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro. Antimicrob Agents Chemother 41: 331– 336. doi: 10.1128/AAC.41.2.331. 9021188 PMC163710 · DOI
  55. [59]Albuquerque P, Nicola AM, Nieves E, Paes HC, Williamson PR, Silva-Pereira I, Casadevall A. 2013. Quorum sensing-mediated, cell density-dependent regulation of growth and virulence in Cryptococcus neoformans. mBio 5: e00986-13– e00913. doi: 10.1128/mBio.00986-13. 24381301 PMC3884061 · DOI
  56. [60]Pierce CG, Uppuluri P, Tristan AR, Wormley FL, Jr., Mowat E, Ramage G, Lopez-Ribot JL. 2008. A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing. Nat Protoc 3: 1494– 1500. doi: 10.1038/nprot.2008.141. 18772877 PMC2741160 · DOI · Paper page
  57. [61]Martinez LR, Casadevall A. 2005. Specific antibody can prevent fungal biofilm formation and this effect correlates with protective efficacy. Infect Immun 73: 6350– 6362. doi: 10.1128/IAI.73.10.6350-6362.2005. 16177306 PMC1230912 · DOI
  58. [62]Bang S, Kwon H, Hwang HS, Park KD, Kim SU, Bahn YS. 2014. 9-O-butyl-13–(4-isopropylbenzyl)berberine, KR-72, is a potent antifungal agent that inhibits the growth of Cryptococcus neoformans by regulating gene expression. PLoS One 9: e109863. doi: 10.1371/journal.pone.0109863. 25302492 PMC4193857 · DOI

Authors
Winski, C. J., Qian, Y., Mobashery, S., & Santiago-Tirado, F. H.
Affiliations
University of Notre Dame (US)
Corresponding author
Santiago-Tirado, Felipe H.
ORCID
Venue
mBio
Publisher
American Society for Microbiology
Published
2022-08-30
Volume
13
Issue
4
Pages
e0153922-e0153922
ISSN
2150-7511 (ISSN-L)
DOI
10.1128/mbio.01539-22
PMC
PMC9426558
OpenAlex
W4283204431
Cited by
37
References
62
Citations by year
2026: 7 · 2025: 7 · 2024: 11 · 2023: 11 · 2022: 1
FWCI
5.41
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • HHS | National Institutes of Health (R01AI104987, R01AI148217, R35GM131685)
  • University of Notre Dame (Start-up funds)
Topics
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
ABC transporters, Cryptococcus neoformans, antifungal resistance, host-pathogen interaction, cryptococcosis, multidrug resistance, fungal pathogenesis, drug efflux
MeSH terms
Animals, Antifungal Agents, Cryptococcosis, Cryptococcus neoformans, Humans, Mycoses, ATP-Binding Cassette Transporters, Drug Resistance, Fungal, Membrane Transport Proteins, Mice

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