Azole resistance in Candida auris: mechanisms and combinatorial therapy.
Candida auris
azole drugs
biofilms
combination therapy
drug synergy
efflux transporters
sphingolipids
Journal
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
ISSN: 1600-0463
Titre abrégé: APMIS
Pays: Denmark
ID NLM: 8803400
Informations de publication
Date de publication:
Aug 2023
Aug 2023
Historique:
received:
22
05
2023
accepted:
02
06
2023
medline:
7
7
2023
pubmed:
20
6
2023
entrez:
20
6
2023
Statut:
ppublish
Résumé
Multidrug resistance Candida auris is a dangerous fungal pathogen that is emerging at an alarming rate and posing serious threats to public health. C. auris is associated with nosocomial infections that cause invasive candidiasis in immunocompromised patients. Several antifungal drugs with distinct mechanisms of action are clinically approved for the treatment of fungal infections. The high rates of intrinsic and acquired drug resistance, particularly to azoles, reported in characterized clinical isolates of C. auris make treatment extremely problematic. In systemic infections, azoles are the first-line treatment for most Candida species; however, the increasing use of drugs results in the frequent emergence of drug resistance. More than 90% of the clinical isolates of C. auris is shown to be highly resistant to azole drugs especially fluconazole, with some strains (types) resistant to all three classes of commonly used antifungals. This presents a huge challenge for researchers in terms of completely understanding the molecular mechanism of azole resistance to develop more efficient drugs. Due to the scarcity of C. auris therapeutic alternatives, the development of successful drug combinations provides an alternative for clinical therapy. Taking advantage of various action mechanisms, such drugs in combination with azole are likely to have synergistic effects, improving treatment efficacy and overcoming C. auris azole drug resistance. In this review, we outline the current state of understanding about the mechanisms of azole resistance mainly fluconazole, and the current advancement in therapeutic approaches such as drug combinations toward C. auris infections.
Substances chimiques
Azoles
0
Fluconazole
8VZV102JFY
Antifungal Agents
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
442-462Subventions
Organisme : ICMR- New Delhi, India, Adhoc
ID : 2021-8947
Organisme : Central University of Punjab, Bathinda
ID : CUPB/CC/PF/20/226
Organisme : Start-Up grant, UGC, New Delhi, India
ID : F.30-583/2021(BSR)
Organisme : Start-Up grant SERB, New Delhi
ID : SRG/2020/000171
Informations de copyright
© 2023 Scandinavian Societies for Pathology, Medical Microbiology and Immunology.
Références
Lone SA, Ahmad A. Candida auris-the growing menace to global health. Mycoses. 2019;62:620-37. https://doi.org/10.1111/myc.12904
Spivak ES, Hanson KE. Candida auris: an emerging fungal pathogen. J Clin Microbiol. 2018;56:e01588-17. https://doi.org/10.1128/JCM.01588-17
Navalkele BD, Revankar S, Chandrasekar P. Candida auris: a worrisome, globally emerging pathogen. Expert Rev Anti Infect Ther. 2017;15:819-27. https://doi.org/10.1080/14787210.2017.1364992
Satoh K, Makimura K, Hasumi Y, Nishiyama Y, Uchida K, Yamaguchi H. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol Immunol. 2009;53:41-4. https://doi.org/10.1111/j.1348-0421.2008.00083.x
Suleyman G, Alangaden GJ. Nosocomial fungal infections: epidemiology, infection control, and prevention. Infect Dis Clin North Am. 2016;30:1023-52. https://doi.org/10.1016/j.idc.2016.07.008
Dahiya S, Chhillar AK, Sharma N, Choudhary P, Punia A, Balhara M, et al. Candida auris and nosocomial infection. Curr Drug Targets. 2019;21:365-73. https://doi.org/10.2174/1389450120666190924155631
Chen Y, Zhao J, Han L, Qi L, Fan W, Liu J, et al. Emergency of fungemia cases caused by fluconazole-resistant Candida auris in Beijing, China. J Infect. 2018;77:561-71. https://doi.org/10.1016/j.jinf.2018.09.002
Chakrabarti A, Sood P, Rudramurthy SM, Chen S, Kaur H, Capoor M, et al. Incidence, characteristics and outcome of ICU-acquired candidemia in India. Intensive Care Med. 2015;41:285-95. https://doi.org/10.1007/s00134-014-3603-2
Alonso-Monge R, Gresnigt MS, Román E, Hube B, Pla J. Candida albicans colonization of the gastrointestinal tract: a double-edged sword. PLoS Pathog. 2021;17:e1009710. https://doi.org/10.1371/journal.ppat.1009710
Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A, Govender NP, et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis. 2017;64:134-40. https://doi.org/10.1093/cid/ciw691
Pekard-Amenitsch S, Schriebl A, Posawetz W, Willinger B, Kölli B, Buzina W. Isolation of Candida auris from ear of otherwise healthy patient, Austria, 2018. Emerg Infect Dis. 2018;24:1596-7. https://doi.org/10.3201/eid2408.180495
Conant MA. Fungal infections in immunocompromised individuals. Dermatol Clin. 1996;14:155-62. https://doi.org/10.1016/S0733-8635(05)70336-3
Nandini D, Manonmoney J, Lavanya J, Leela KV. Sujith. A study on prevalence and characterization of Candida species in immunocompromised patients. J Pure Appl Microbiol. 2021;15:2065-72. https://doi.org/10.22207/JPAM.15.4.29
Piatti G, Sartini M, Cusato C, Schito AM. Colonization by Candida auris in critically ill patients: role of cutaneous and rectal localization during an outbreak. J Hosp Infect. 2022;120:85-9. https://doi.org/10.1016/j.jhin.2021.11.004
Hanson BM, Dinh AQ, Tran TT, Arenas S, Pronty D, Gershengorn HB, et al. Candida auris invasive infections during a COVID-19 case surge. Antimicrob Agents Chemother. 2021;65:e0114621. https://doi.org/10.1128/AAC.01146-21
Chowdhary A, Tarai B, Singh A, Sharma A. Multidrug-resistant Candida auris infections in critically ill coronavirus disease patients, India, April-July 2020. Emerg Infect Dis. 2020;26:2694-6. https://doi.org/10.3201/eid2611.203504
Fisher MC, Alastruey-Izquierdo A, Berman J, Bicanic T, Bignell EM, Bowyer P, et al. Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol. 2022;20:557-71. https://doi.org/10.1038/s41579-022-00720-1
Chakrabarti A, Sood P. On the emergence, spread and resistance of Candida auris: host, pathogen and environmental tipping points. J Med Microbiol. 2021;70:001318. https://doi.org/10.1099/jmm.0.001318
Kordalewska M, Perlin DS. Identification of drug resistant Candida auris. Front Microbiol. 2019;10:1918. https://doi.org/10.3389/fmicb.2019.01918
Mizusawa M, Miller H, Green R, Lee R, Durante M, Perkins R, et al. Can multidrug-resistant Candida auris be reliably identified in clinical microbiology laboratories? J Clin Microbiol. 2017;55:638-40. https://doi.org/10.1128/JCM.02202-16
Yadav A, Singh A, Chowdhary A. Isolation of Candida auris in clinical specimens. Methods Mol Biol. 2022;2517:3-20. https://doi.org/10.1007/978-1-0716-2417-3_1
Kathuria S, Singh PK, Sharma C, Prakash A, Masih A, Kumar A, et al. Multidrug-resistant Candida auris misidentified as Candida haemulonii: characterization by matrix-assisted laser desorption ionization-time of flight mass spectrometry and DNA sequencing and its antifungal susceptibility profile variability by vitek 2, CLSI broth microdilution, and etest method. J Clin Microbiol. 2015;53:1823-30. https://doi.org/10.1128/JCM.00367-15
Kumar A, Sachu A, Mohan K, Vinod V, Dinesh K, Karim S. Simple low cost differentiation of Candida auris from Candida haemulonii complex using CHROMagar Candida medium supplemented with Pal's medium. Rev Iberoam Micol. 2017;34:109-11. https://doi.org/10.1016/j.riam.2016.11.004
De Jong AW, Dieleman C, Carbia M, Tap RM, Hagen F. Performance of two novel chromogenic media for the identification of multidrug-resistant Candida auris compared with other commercially available formulations. J Clin Microbiol. 2021;59:e03220-20. https://doi.org/10.1128/JCM.03220-20
Lockhart SR, Lyman MM, Joseph SD. Tools for detecting a “superbug”: updates on Candida auris testing. J Clin Microbiol. 2022;60:e0080821. https://doi.org/10.1128/jcm.00808-21
Santos MAS, Tuite MF. The CUG codon is decoded in vivo as serine and not leucine in Candida albicans. Nucleic Acids Res. 1995;23:1481-6. https://doi.org/10.1093/nar/23.9.1481
Skrzypek MS, Binkley J, Binkley G, Miyasato SR, Simison M, Sherlock G. The Candida Genome Database (CGD): incorporation of assembly 22, systematic identifiers and visualization of high throughput sequencing data. Nucleic Acids Res. 2017;45:D592-6. https://doi.org/10.1093/nar/gkw924
Muñoz JF, Gade L, Chow NA, Loparev VN, Juieng P, Berkow EL, et al. Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species. Nat Commun. 2018;9:5346. https://doi.org/10.1038/s41467-018-07779-6
Allert S, Schulz D, Kämmer P, Großmann P, Wolf T, Schäuble S, et al. From environmental adaptation to host survival: attributes that mediate pathogenicity of Candida auris. Virulence. 2022;13:191-214. https://doi.org/10.1080/21505594.2022.2026037
Forsberg K, Woodworth K, Walters M, Berkow EL, Jackson B, Chiller T, et al. Candida auris: the recent emergence of a multidrug-resistant fungal pathogen. Med Mycol. 2019;57:1-12. https://doi.org/10.1093/mmy/myy054
Jackson BR, Chow N, Forsberg K, Litvintseva AP, Lockhart SR, Welsh R, et al. On the origins of a species: what might explain the rise of Candida auris? J Fungi. 2019;5:58. https://doi.org/10.3390/jof5030058
Chow NA, Muñoz JF, Gade L, Berkow EL, Li X, Welsh RM, et al. Tracing the evolutionary history and global expansion of Candida auris using population genomic analyses. MBio. 2020;11:e03364-19. https://doi.org/10.1128/mBio.03364-19
Du H, Bing J, Hu T, Ennis CL, Nobile CJ, Huang G. Candida auris: epidemiology, biology, antifungal resistance, and virulence. PLoS Pathog. 2020;16:e1008921. https://doi.org/10.1371/journal.ppat.1008921
Chow NA, De Groot T, Badali H, Abastabar M, Chiller TM, Meis JF. Potential fifth clade of Candida auris, Iran, 2018. Emerg Infect Dis. 2019;25:1780-1. https://doi.org/10.3201/eid2509.190686
Muñoz JF, Welsh RM, Shea T, Batra D, Gade L, Howard D, et al. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris. Genetics. 2021;218:iyab029. https://doi.org/10.1093/genetics/iyab029
Welsh RM, Sexton DJ, Forsberg K, Vallabhaneni S, Litvintseva A. Insights into the unique nature of the east asian clade of the emerging pathogenic yeast Candida auris. J Clin Microbiol. 2018;57:e00007-19. https://doi.org/10.1128/JCM.00007-19
CDC. Antibiotic resistance threats in the United States 2019. Vero Beach, FL: CDC; 2019. p. 5.
Kathiravan MK, Salake AB, Chothe AS, Dudhe PB, Watode RP, Mukta MS, et al. The biology and chemistry of antifungal agents: a review. Bioorg Med Chem. 2012;20:5678-98. https://doi.org/10.1016/j.bmc.2012.04.045
Nocua-Báez LC, Uribe-Jerez P, Tarazona-Guaranga L, Robles R, Cortés JA. Azoles of then and now: a review. Rev Chilena Infectol. 2020;37:219-30. https://doi.org/10.4067/s0716-10182020000300219
Baginski M, Resat H, McCammon JA. Molecular properties of amphotericin B membrane channel: a molecular dynamics simulation. Mol Pharmacol. 1997;52:560-70. https://doi.org/10.1124/mol.52.4.560
Sawistowska-Schröder ET, Kerridge D, Perry H. Echinocandin inhibition of 1,3-β-D-glucan synthase from Candida albicans. FEBS Lett. 1984;173:134-8. https://doi.org/10.1016/0014-5793(84)81032-7
Perlin DS. Current perspectives on echinocandin class drugs. Future Microbiol. 2011;6:441-57. https://doi.org/10.2217/fmb.11.19
Frías-De-león MG, Hernández-Castro R, Vite-Garín T, Arenas R, Bonifaz A, Castañón-Olivares L, et al. Antifungal resistance in Candida auris: Molecular determinants. Antibiotics. 2020;9:568. https://doi.org/10.3390/antibiotics9090568
Chowdhary A, Prakash A, Sharma C, Kordalewska M, Kumar A, Sarma S, et al. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother. 2018;73:891-9. https://doi.org/10.1093/jac/dkx480
Allen D, Wilson D, Drew R, Perfect J. Azole antifungals: 35 years of invasive fungal infection management. Expert Rev Anti Infect Ther. 2015;13:787-98. https://doi.org/10.1586/14787210.2015.1032939
Musiol R, Kowalczyk W. Azole antimycotics-a highway to new drugs or a dead end? Curr Med Chem. 2012;19:1378-88. https://doi.org/10.2174/092986712799462621
Shafiei M, Peyton L, Hashemzadeh M, Foroumadi A. History of the development of antifungal azoles: a review on structures, SAR, and mechanism of action. Bioorg Chem. 2020;104:104240. https://doi.org/10.1016/j.bioorg.2020.104240
Sagatova AA, Keniya MV, Wilson RK, Monk BC, Tyndall JDA. Structural insights into binding of the antifungal drug fluconazole to Saccharomyces cerevisiae lanosterol 14α-demethylase. Antimicrob Agents Chemother. 2015;59:4982-9. https://doi.org/10.1128/AAC.00925-15
Hargrove TY, Wawrzak Z, Lamb DC, Guengerich FP, Lepesheva GI. Structure-functional characterization of cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and molecular basis for the development of antifungal drugs. J Biol Chem. 2015;290:23916-34. https://doi.org/10.1074/jbc.M115.677310
Hoekstra WJ, Garvey EP, Moore WR, Rafferty SW, Yates CM, Schotzinger RJ. Design and optimization of highly-selective fungal CYP51 inhibitors. Bioorg Med Chem Lett. 2014;24:3455-8. https://doi.org/10.1016/j.bmcl.2014.05.068
Ji H, Zhang W, Zhou Y, Zhang M, Zhu J, Song Y, et al. A three-dimensional model of lanosterol 14α-demethylase of Candida albicans and its interaction with azole antifungals. J Med Chem. 2000;43:2493-505. https://doi.org/10.1021/jm990589g
Podust LM, Poulos TL, Waterman MR. Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc Natl Acad Sci USA. 2001;98:3068-73. https://doi.org/10.1073/pnas.061562898
Bravo Ruiz G, Lorenz A. What do we know about the biology of the emerging fungal pathogen of humans Candida auris? Microbiol Res. 2021;242:126621. https://doi.org/10.1016/j.micres.2020.126621
Mitropoulos KA, Gibbons GF, Reeves BEA. Lanosterol 14α-demethylase. Similarity of the enzyme system from yeast and rat liver. Steroids. 1976;27:821-9. https://doi.org/10.1016/0039-128X(76)90141-0
Healey KR, Kordalewska M, Ortigosa CJ, Singh A, Berrío I, Chowdhary A, et al. Limited ERG11 mutations identified in isolates of Candida auris directly contribute to reduced azole susceptibility. Antimicrob Agents Chemother. 2018;62:e01427-18. https://doi.org/10.1128/AAC.01427-18
Li J, Coste AT, Liechti M, Bachmann D, Sanglard D, Lamoth F. Novel ERG11 and TAC1b mutations associated with azole resistance in Candida auris. Antimicrob Agents Chemother. 2023;65:e02663-20. https://doi.org/10.1128/AAC.02663-20
Warrilow AG, Nishimoto AT, Parker JE, Price CL, Flowers SA, Kelly DE, et al. The evolution of Azole resistance in Candida albicans Sterol 14-demethylase (CYP51) through incremental amino acid substitutions. Antimicrob Agents Chemother. 2019;63:e02586-18. https://doi.org/10.1128/AAC.02586-18
Khademi P, Ranji N, Rahnamay Roodposhti F. Mutations in hotspot regions of ERG11 gene in fluconazole resistant isolates of Candida albicans in Guilan Province, Northern Iran. Mol Gen Microbiol Virol. 2017;32:241-5. https://doi.org/10.3103/S0891416817040085
Flowers SA, Colón B, Whaley SG, Schuler MA, David Rogers P. Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans. Antimicrob Agents Chemother. 2015;59:450-60. https://doi.org/10.1128/AAC.03470-14
Lescar J, Meyer I, Akshita K, Srinivasaraghavan K, Verma C, Palous M, et al. Aspergillus fumigatus harbouring the sole Y121F mutation shows decreased susceptibility to voriconazole but maintained susceptibility to itraconazole and posaconazole. J Antimicrob Chemother. 2014;69:3244-7. https://doi.org/10.1093/jac/dku316
Rybak JM, Sharma C, Doorley LA, Barker KS, Palmer GE, Rogers PD. Delineation of the direct contribution of Candida auris ERG11 mutations to clinical triazole resistance. Microbiol Spectr. 2021;9:e0158521. https://doi.org/10.1128/spectrum.01585-21
Rhodes J, Abdolrasouli A, Farrer RA, Cuomo CA, Aanensen DM, Armstrong-James D, et al. Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris article. Emerg Microbes Infect. 2018;7:43. https://doi.org/10.1038/s41426-018-0045-x
Hou X, Lee A, Jiménez-Ortigosa C, Kordalewska M, Perlin DS, Zhao Y. Rapid detection of ERG11-associated azole resistance and FKS-associated echinocandin resistance in Candida auris. Antimicrob Agents Chemother. 2019;63:e01811-18. https://doi.org/10.1128/AAC.01811-18
Kwon YJ, Shin JH, Byun SA, Choi MJ, Won EJ, Lee D, et al. Candida auris clinical isolates from South Korea: identification, antifungal susceptibility, and genotyping. J Clin Microbiol. 2018;57:e01624-18. https://doi.org/10.1128/JCM.01624-18
Song JL, Harry JB, Eastman RT, Oliver BG, White TC. The Candida albicans lanosterol 14-α-demethylase (ERG11) gene promoter is maximally induced after prolonged growth with antifungal drugs. Antimicrob Agents Chemother. 2004;48:1136-44. https://doi.org/10.1128/AAC.48.4.1136-1144.2004
Oliver BG, Song JL, Choiniere JH, White TC. Cis-acting elements within the Candida albicans ERG11 promoter mediate the azole response through transcription factor Upc2p. Eukaryot Cell. 2007;6:2231-9. https://doi.org/10.1128/EC.00331-06
Balzi E, Goffeau A. Yeast multidrug resistance: the PDR network. J Bioenerg Biomembr. 1995;27:71-6. https://doi.org/10.1007/BF02110333
Kolaczkowski M, Kolaczkowska A, Luczynski J, Witek S, Goffeau A. In vivo characterization of the drug resistance profile of the major ABC transporters and other components of the yeast pleiotropic drug resistance network. Microb Drug Resist. 1998;4:143-58. https://doi.org/10.1089/mdr.1998.4.143
Carvajal E, Van Den Hazel HB, Cybularz-Kolaczkowska A, Balzi E, Goffeau A. Molecular and phenotypic: characterization of yeast PDR1 mutants that show hyperactive transcription of various ABC multidrug transporter genes. Mol Gen Genet. 1997;256:406-15. https://doi.org/10.1007/s004380050584
Caudle KE, Barker KS, Wiederhold NP, Xu L, Homayouni R, Rogers PD. Genomewide expression profile analysis of the Candida glabrata Pdr1 regulon. Eukaryot Cell. 2010;10:373-83. https://doi.org/10.1128/EC.00073-10
Ferrari S, Sanguinetti M, Torelli R, Posteraro B, Sanglard D. Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata. PLoS One. 2011;6:e17589. https://doi.org/10.1371/journal.pone.0017589
Chen LM, Xu YH, Zhou CL, Zhao J, Li CY, Wang R. 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. 2010;38:536-45. https://doi.org/10.1177/147323001003800216
Coste AT, Karababa M, Ischer F, Bille J, Sanglard D. TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2. Eukaryot Cell. 2004;3:1639-52. https://doi.org/10.1128/EC.3.6.1639-1652.2004
Sanglard D. Diagnosis of antifungal drug resistance mechanisms in fungal pathogens: transcriptional gene regulation. Curr Fungal Infect Rep. 2011;5:157-67. https://doi.org/10.1007/s12281-011-0055-9
Morschhäuser J, Barker KS, Liu TT, Blaß-Warmuth J, Homayouni R, Rogers PD. The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog. 2007;3:e164. https://doi.org/10.1371/journal.ppat.0030164
Ni Q, Wang C, Tian Y, Dong D, Jiang C, Mao E, et al. CgPDR1 gain-of-function mutations lead to azole-resistance and increased adhesion in clinical Candida glabrata strains. Mycoses. 2018;61:430-40. https://doi.org/10.1111/myc.12756
Liu JY, Wei B, Wang Y, Shi C, Li WJ, Zhao Y, et al. The H741D mutation in Tac1p contributes to the upregulation of CDR1 and CDR2 expression in Candida albicans. Braz J Microbiol. 2020;51:1553-61. https://doi.org/10.1007/s42770-020-00336-8
Rybak JM, Muñoz JF, Barker KS, Parker JE, Esquivel BD, Berkow EL, et al. Mutations in TAC1B: a novel genetic determinant of clinical fluconazole resistance in Candida auris. MBio. 2020;11:e00365-20. https://doi.org/10.1128/mBio.00365-20
Wasi M, Kumar Khandelwal N, Moorhouse AJ, Nair R, Vishwakarma P, Bravo Ruiz G, et al. ABC transporter genes show upregulated expression in drug-resistant clinical isolates of Candida auris: a genome-wide characterization of atp-binding cassette (abc) transporter genes. Front Microbiol. 2019;10:1445. https://doi.org/10.3389/fmicb.2019.01445
Ben-Ami R, Berman J, Novikov A, Bash E, Shachor-Meyouhas Y, Zakin S, et al. Multidrug-resistant Candida haemulonii and C. auris, Tel Aviv, Israel. Emerg Infect Dis. 2017;23:195-203. https://doi.org/10.3201/eid2302.161486
Rybak JM, Doorley LA, Nishimoto AT, Barker KS, Palmer GE, Rogers PD. Abrogation of triazole resistance upon deletion of CDR1 in a clinical isolate of Candida auris. Antimicrob Agents Chemother. 2019;63:e00057-19. https://doi.org/10.1128/aac.00057-19
Jacobs SE, Jacobs JL, Dennis EK, Taimur S, Rana M, Patel D, et al. Candida auris pan-drug-resistant to four classes of antifungal agents. Antimicrob Agents Chemother. 2022;66:e0005322. https://doi.org/10.1128/aac.00053-22
Silver PM, Oliver BG, White TC. Role of Candida albicans transcription factor Upc2p in drug resistance and sterol metabolism. Eukaryot Cell. 2004;3:1391-7. https://doi.org/10.1128/EC.3.6.1391-1397.2004
Mayr E-M, Ramírez-Zavala B, Krüger I, Morschhäuser J. A zinc cluster transcription factor contributes to the intrinsic fluconazole resistance of Candida auris. mSphere. 2020;5:e00279-20. https://doi.org/10.1128/msphere.00279-20
Li J, Coste AT, Bachmann D, Sanglard D, Lamoth F. Deciphering the Mrr1/Mdr1 pathway in azole resistance of Candida auris. Antimicrob Agents Chemother. 2022;66:e0006722. https://doi.org/10.1128/aac.00067-22
Kwon-Chung KJ, Chang YC. Aneuploidy and drug resistance in pathogenic fungi. PLoS Pathog. 2012;8:e1003022. https://doi.org/10.1371/journal.ppat.1003022
Bing J, Hu T, Zheng Q, Muñoz JF, Cuomo CA, Huang G. Experimental evolution identifies adaptive aneuploidy as a mechanism of fluconazole resistance in Candida auris. Antimicrob Agents Chemother. 2021;65:e01466-20. https://doi.org/10.1128/AAC.01466-20
Selmecki A, Gerami-Nejad M, Paulson C, Forche A, Berman J. An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1. Mol Microbiol. 2008;68:624-41. https://doi.org/10.1111/j.1365-2958.2008.06176.x
Carolus H, Pierson S, Muñoz JF, Subotić A, Cruz RB, Cuomo CA, et al. Genome-wide analysis of experimentally evolved Candida auris reveals multiple novel mechanisms of multidrug resistance. MBio. 2021;12:e03333-20. https://doi.org/10.1128/mBio.03333-20
Burrack LS, Todd RT, Soisangwan N, Wiederhold NP, Selmecki A. Genomic diversity across Candida auris clinical isolates shapes rapid development of antifungal resistance in vitro and in vivo. MBio. 2022;13:e0084222. https://doi.org/10.1128/mbio.00842-22
Bhattacharya S, Holowka T, Orner EP, Fries BC. Gene duplication associated with increased fluconazole tolerance in Candida auris cells of advanced generational age. Sci Rep. 2019;9:5052. https://doi.org/10.1038/s41598-019-41513-6
White TC. 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. 1997;41:1482-7. https://doi.org/10.1128/aac.41.7.1482
Pereira R, dos Santos Fontenelle RO, de Brito EHS, de Morais SM. Biofilm of Candida albicans: formation, regulation and resistance. J Appl Microbiol. 2021;131:11-22. https://doi.org/10.1111/jam.14949
Silva S, Negri M, Henriques M, Oliveira R, Williams DW, Azeredo J. Adherence and biofilm formation of non-Candida albicans Candida species. Trends Microbiol. 2011;19:241-7. https://doi.org/10.1016/j.tim.2011.02.003
Nobile CJ, Johnson AD. Candida albicans biofilms and human disease. Annu Rev Microbiol. 2015;69:71-92. https://doi.org/10.1146/annurev-micro-091014-104330
Horton MV, Nett JE. Candida auris infection and biofilm formation: going beyond the surface. Curr Clin Microbiol Rep. 2020;7:51-6. https://doi.org/10.1007/s40588-020-00143-7
Kaur J, Nobile CJ. Antifungal drug-resistance mechanisms in Candida biofilms. Curr Opin Microbiol. 2023;71:102237. https://doi.org/10.1016/j.mib.2022.102237
Dominguez EG, Zarnowski R, Choy HL, Zhao M, Sanchez H, Nett JE, et al. Conserved role for biofilm matrix polysaccharides in Candida auris drug resistance. mSphere. 2019;4:e00680-18. https://doi.org/10.1128/mspheredirect.00680-18
Kean R, Ramage G. Combined antifungal resistance and biofilm tolerance: the global threat of Candida auris. mSphere. 2019;4:e00458-19. https://doi.org/10.1128/msphere.00458-19
Alves R, Barata-Antunes C, Casal M, Brown AJP, van Dijck P, Paiva S. Adapting to survive: how Candida overcomes host-imposed constraints during human colonization. PLoS Pathog. 2020;16:e1008478. https://doi.org/10.1371/journal.ppat.1008478
Sherry L, Ramage G, Kean R, Borman A, Johnson EM, Richardson MD, et al. Biofilm-forming capability of highly virulent, multidrug-resistant Candida auris. Emerg Infect Dis. 2017;23:328-31. https://doi.org/10.3201/eid2302.161320
Kean R, Delaney C, Sherry L, Borman A, Johnson EM, Richardson MD, et al. Transcriptome assembly and profiling of Candida auris reveals novel insights into biofilm-mediated resistance. mSphere. 2018;3:e00334-18.
Borman AM, Szekely A, Johnson EM. Comparative pathogenicity of United Kingdom isolates of the emerging pathogen Candida auris and other key pathogenic Candida species. mSphere. 2016;1:e00189-16. https://doi.org/10.1128/msphere.00189-16
Singh R, Kaur M, Chakrabarti A, Shankarnarayan SA, Rudramurthy SM. Biofilm formation by Candida auris isolated from colonising sites and candidemia cases. Mycoses. 2019;62:706-9. https://doi.org/10.1111/myc.12947
Nobile CJ, Fox EP, Nett JE, Sorrells TR, Mitrovich QM, Hernday AD, et al. A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell. 2012;148:126-38. https://doi.org/10.1016/j.cell.2011.10.048
Ramage G, Bachmann S, Patterson TF, Wickes BL, López-Ribot JL. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J Antimicrob Chemother. 2002;49:973-80. https://doi.org/10.1093/jac/dkf049
Chawla J, Shrivastav A. Antimicrobial tolerance in biofilms. In: Shah MP, editor. Application of biofilms in applied microbiology. Amsterdam: Elsevier Science; 2022. p. 235-55. https://doi.org/10.1016/B978-0-323-90513-8.00011-X
Ciofu O, Moser C, Jensen PØ, Høiby N. Tolerance and resistance of microbial biofilms. Nat Rev Microbiol. 2022;20:621-35. https://doi.org/10.1038/s41579-022-00682-4
Taff HT, Nett JE, Zarnowski R, Ross KM, Sanchez H, Cain MT, et al. A Candida biofilm-induced pathway for matrix glucan delivery: implications for drug resistance. PLoS Pathog. 2012;8:e1002848. https://doi.org/10.1371/journal.ppat.1002848
Dickson RC. Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast. J Lipid Res. 2008;49:909-21. https://doi.org/10.1194/jlr.r800003-jlr200
Singh A, Yadav V, Prasad R. Comparative lipidomics in clinical isolates of Candida albicans reveal crosstalk between mitochondria, cell wall integrity and azole resistance. PLoS One. 2012;7:e39812. https://doi.org/10.1371/journal.pone.0039812
Singh A, Prasad R. Comparative lipidomics of azole sensitive and resistant clinical isolates of Candida albicans reveals unexpected diversity in molecular lipid imprints. PLoS One. 2011;6:e19266. https://doi.org/10.1371/journal.pone.0019266
Zhai P, Song J, Gao L, Lu L. A sphingolipid synthesis-related protein OrmA in Aspergillus fumigatus is responsible for azole susceptibility and virulence. Cell Microbiol. 2019;21:e13092. https://doi.org/10.1111/cmi.13092
Hughes WE, Pocklington MJ, Orr E, Paddon CJ. Mutations in the Saccharomyces cerevisiae gene SAC1 cause multiple drug sensitivity. Yeast. 1999;15:1111-24. https://doi.org/10.1002/(SICI)1097-0061(199908)15:11<1111::AID-YEA440>3.0.CO;2-H
Kumar M, Singh A, Kumari S, Kumar P, Wasi M, Mondal AK, et al. Sphingolipidomics of drug resistant Candida auris clinical isolates reveal distinct sphingolipid species signatures. Biochim Biophys Acta Mol Cell Biol Lipids. 2021;1866:158815. https://doi.org/10.1016/j.bbalip.2020.158815
Khandelwal NK, Sarkar P, Gaur NA, Chattopadhyay A, Prasad R. Phosphatidylserine decarboxylase governs plasma membrane fluidity and impacts drug susceptibilities of Candida albicans cells. Biochim Biophys Acta Biomembr. 2018;1860:2308-19. https://doi.org/10.1016/j.bbamem.2018.05.016
Kappagoda S, Singh U, Blackburn BG. Antiparasitic therapy. Mayo Clin Proc. 2011;86:561-83. https://doi.org/10.4065/mcp.2011.0203
Tängdén T. Combination antibiotic therapy for multidrug-resistant gram-negative bacteria. Ups J Med Sci. 2014;119:149-53. https://doi.org/10.3109/03009734.2014.899279
Shyr ZA, Cheng YS, Lo DC, Zheng W. Drug combination therapy for emerging viral diseases. Drug Discov Today. 2021;26:2367-76. https://doi.org/10.1016/j.drudis.2021.05.008
Mokhtari RB, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, et al. Combination therapy in combating cancer. Oncotarget. 2017;8:38022-43.
Ademe M, Girma F. Candida auris: from multidrug resistance to pan-resistant strains. Infect Drug Resist. 2020;13:1287-94. https://doi.org/10.2147/IDR.S249864
Garcia-Bustos V, Cabanero-Navalon MD, Ruiz-Saurí A, Ruiz-Gaitán AC, Salavert M, Tormo M, et al. What do we know about Candida auris? State of the art, knowledge gaps, and future directions. Microorganisms. 2021;9:2177. https://doi.org/10.3390/microorganisms9102177
Sanyaolu A, Okorie C, Marinkovic A, Abbasi AF, Prakash S, Mangat J, et al. Candida auris: an overview of the emerging drug-resistant fungal infection. Infect Chemother. 2022;54:236-46. https://doi.org/10.3947/IC.2022.0008
Yang M, Jaaks P, Dry J, Garnett M, Menden MP, Saez-Rodriguez J. Stratification and prediction of drug synergy based on target functional similarity. NPJ Syst Biol Appl. 2020;6:16. https://doi.org/10.1038/s41540-020-0136-x
Mäkelä P, Zhang SM, Rudd SG. Drug synergy scoring using minimal dose response matrices. BMC Res Notes. 2021;14:27. https://doi.org/10.1186/s13104-021-05445-7
Vitale RG. Role of antifungal combinations in difficult to treat Candida infections. J Fungi. 2021;7:731. https://doi.org/10.3390/jof7090731
Rather IA, Sabir JSM, Asseri AH, Ali S. Antifungal activity of human cathelicidin LL-37, a membrane disrupting peptide, by triggering oxidative stress and cell cycle arrest in Candida auris. J Fungi. 2022;8:204. https://doi.org/10.3390/jof8020204
Caballero U, Kim S, Eraso E, Quindós G, Vozmediano V, Schmidt S, et al. In vitro synergistic interactions of isavuconazole and echinocandins against Candida auris. Antibiotics. 2021;10:355. https://doi.org/10.3390/antibiotics10040355
O'Brien B, Liang J, Chaturvedi S, Jacobs JL, Chaturvedi V. Pan-resistant Candida auris: New York subcluster susceptible to antifungal combinations. Lancet Microbe. 2020;1:e193-4. https://doi.org/10.1016/S2666-5247(20)30090-2
Iyer KR, Camara K, Daniel-Ivad M, Trilles R, Pimentel-Elardo SM, Fossen JL, et al. An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris. Nat Commun. 2020;11:6429. https://doi.org/10.1038/s41467-020-20183-3
Shahi G, Kumar M, Skwarecki AS, Edmondson M, Banerjee A, Usher J, et al. Fluconazole resistant Candida auris clinical isolates have increased levels of cell wall chitin and increased susceptibility to a glucosamine-6-phosphate synthase inhibitor. Cell Surf. 2022;8:100076. https://doi.org/10.1016/j.tcsw.2022.100076
Dekkerová J, Černáková L, Kendra S, Borghi E, Ottaviano E, Willinger B, et al. Farnesol boosts the antifungal effect of fluconazole and modulates resistance in Candida auris through regulation of the CDR1 and ERG11 genes. J Fungi. 2022;8:783. https://doi.org/10.3390/jof8080783
Mahendrarajan V, Bari VK. A critical role of farnesol in the modulation of amphotericin B and aureobasidin A antifungal drug susceptibility. Mycology. 2022;13:305-17. https://doi.org/10.1080/21501203.2022.2138599
Wiederhold NP, Lockhart SR, Najvar LK, Berkow EL, Jaramillo R, Olivo M, et al. The fungal Cyp51-specific inhibitor VT-1598 demonstrates in vitro and in vivo activity against Candida auris. Antimicrob Agents Chemother. 2019;63:e02233-18. https://doi.org/10.1128/AAC.02233-18
Rudramurthy SM, Colley T, Abdolrasouli A, Ashman J, Dhaliwal M, Kaur H, et al. In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris. J Antimicrob Chemother. 2019;74:2943-9. https://doi.org/10.1093/jac/dkz280
Ni T, Chi X, Xie F, Li L, Wu H, Hao Y, et al. Design, synthesis, and evaluation of novel tetrazoles featuring isoxazole moiety as highly selective antifungal agents. Eur J Med Chem. 2023;246:115007. https://doi.org/10.1016/j.ejmech.2022.115007
Gowri M, Jayashree B, Jeyakanthan J, Girija EK. Sertraline as a promising antifungal agent: inhibition of growth and biofilm of Candida auris with special focus on the mechanism of action in vitro. J Appl Microbiol. 2020;128:426-37. https://doi.org/10.1111/jam.14490
Nagaraj S, Manivannan S, Narayan S. Potent antifungal agents and use of nanocarriers to improve delivery to the infected site: a systematic review. J Basic Microbiol. 2021;61:849-73. https://doi.org/10.1002/jobm.202100204
Arias LS, Brown JL, Butcher MC, Delaney C, Monteiro DR, Ramage G. A nanocarrier system that potentiates the effect of miconazole within different interkingdom biofilms. J Oral Microbiol. 2020;12:1771071. https://doi.org/10.1080/20002297.2020.1771071
Caldeirão ACM, Araujo HC, Tomasella CM, Sampaio C, Oliveira MJDS, Ramage G, et al. Effects of antifungal carriers based on chitosan-coated iron oxide nanoparticles on microcosm biofilms. Antibiotics. 2021;10:588. https://doi.org/10.3390/antibiotics10050588
El Rabey HA, Almutairi FM, Alalawy AI, Al-Duais MA, Sakran MI, Zidan NS, et al. Augmented control of drug-resistant Candida spp. via fluconazole loading into fungal chitosan nanoparticles. Int J Biol Macromol. 2019;141:141-516. https://doi.org/10.1016/j.ijbiomac.2019.09.036
Kolge H, Patil G, Jadhav S, Ghormade V. A pH-tuned chitosan-PLGA nanocarrier for fluconazole delivery reduces toxicity and improves efficacy against resistant Candida. Int J Biol Macromol. 2023;227:453-61. https://doi.org/10.1016/j.ijbiomac.2022.12.139
Elmotasem H, Awad GEA. A stepwise optimization strategy to formulate in situ gelling formulations comprising fluconazole-hydroxypropyl-beta-cyclodextrin complex loaded niosomal vesicles and Eudragit nanoparticles for enhanced antifungal activity and prolonged ocular delivery. Asian J Pharm Sci. 2020;15:617-36. https://doi.org/10.1016/j.ajps.2019.09.003
Sutar Y, Nabeela S, Singh S, Alqarihi A, Solis N, Ghebremariam T, et al. Niclosamide-loaded nanoparticles disrupt Candida biofilms and protect mice from mucosal candidiasis. PLoS Biol. 2022;20:e3001762. https://doi.org/10.1371/journal.pbio.3001762
Kim JH, Cheng LW, Chan KL, Tam CC, Mahoney N, Friedman M, et al. Antifungal drug repurposing. Antibiotics. 2020;9:812. https://doi.org/10.3390/antibiotics9110812
Zhang Q, Liu F, Zeng M, Mao Y, Song Z. Drug repurposing strategies in the development of potential antifungal agents. Appl Microbiol Biotechnol. 2021;105:5259-79. https://doi.org/10.1007/s00253-021-11407-7
Aghaei Gharehbolagh S, Izadi A, Talebi M, Sadeghi F, Zarrinnia A, Zarei F, et al. New weapons to fight a new enemy: a systematic review of drug combinations against the drug-resistant fungus Candida auris. Mycoses. 2021;64:1308-16. https://doi.org/10.1111/myc.13277
Pathirana RU, Friedman J, Norris HL, Salvatori O, McCall AD, Kay J, et al. Fluconazole-resistant Candida auris is susceptible to salivary histatin 5 killing and to intrinsic host defenses. Antimicrob Agents Chemother. 2018;62:e01872-17. https://doi.org/10.1128/AAC.01872-17
Cha R, Sobel JD. Fluconazole for the treatment of candidiasis: 15 years experience. Expert Rev Anti Infect Ther. 2004;2:357-66. https://doi.org/10.1586/14787210.2.3.357
Song J, Liu X, Li R. Sphingolipids: regulators of azole drug resistance and fungal pathogenicity. Mol Microbiol. 2020;114:891-905. https://doi.org/10.1111/mmi.14586
Gao J, Wang H, Li Z, Wong AHH, Wang YZ, Guo Y, et al. Candida albicans gains azole resistance by altering sphingolipid composition. Nat Commun. 2018;9:4495. https://doi.org/10.1038/s41467-018-06944-1
Williamson B, Wilk A, Guerrero KD, Mikulski TD, Elias TN, Sawh I, et al. Impact of Erg11 amino acid substitutions identified in Candida auris clade III isolates on triazole drug susceptibility. Antimicrob Agents Chemother. 2022;66:e0162421. https://doi.org/10.1128/AAC.01624-21
Fakhim H, Chowdhary APA. In vitro interactions of echinocandins with triazoles against multidrug-resistant Candida auris. Antimicrob Agents Chemother. 2017;61:e01056-17.
Pfaller MA, Messer SA, Deshpande LM, Rhomberg PR, Utt EA, Castanheira M. Evaluation of synergistic activity of isavuconazole or voriconazole plus anidulafungin and the occurrence and genetic characterization of Candida auris detected in a surveillance program. Antimicrob Agents Chemother. 2021;65:e02031-20. https://doi.org/10.1128/AAC.02031-20
Khaled JM, Alharbi NS, Kadaikunnan S, Alobaidi AS, Nauman K, Ghilan AM, et al. Distribution of Candida infections in patients and evaluation of the synergic interactions of some drugs against emerging fluconazole- and caspofungin-resistant C. auris. J King Saud Univ Sci. 2023;35:102617. https://doi.org/10.1016/j.jksus.2023.102617
Caballero U, Eraso E, Quindós G, Schmidt S, Jauregizar N. PK/PD modeling and simulation of the in vitro activity of the combinations of isavuconazole with echinocandins against Candida auris. CPT Pharmacometrics Syst Pharmacol. 2023;2:1-13. https://doi.org/10.1002/psp4.12949
O'Brien B, Chaturvedi S, Chaturvedi V. In vitro evaluation of antifungal drug combinations against multidrug-resistant Candida auris isolates from New York outbreak. Antimicrob Agents Chemother. 2020;64:1-14. https://doi.org/10.1128/AAC.02195-19
Cheng Y, Roma S, Shen M, Fernandes M, Tsang PS, Forbes E, et al. Identification of antifungal compounds against multidrug-resistant Candida auris utilizing a high-throughput drug-repurposing screen. Antimicrob Agents Chemother. 2021;65:e01305-20.
De Oliveira HC, Monteiro MC, Rossi SA, Pemán J, Ruiz-Gaitán A, Mendes-Giannini MJS, et al. Identification of off-patent compounds that present antifungal activity against the emerging fungal pathogen Candida auris. Front Cell Infect Microbiol. 2019;9:83. https://doi.org/10.3389/fcimb.2019.00083
Tits J, Cools F, De Cremer K, De Brucker K, Berman J, Verbruggen K, et al. Combination of miconazole and Domiphen bromide is fungicidal against biofilms of resistant Candida spp. Antimicrob Agents Chemother. 2020;64:e01296-20.
Eldesouky HE, Li X, Abutaleb NS, Mohammad H, Seleem MN. Synergistic interactions of sulfamethoxazole and azole antifungal drugs against emerging multidrug-resistant Candida auris. Int J Antimicrob Agents. 2018;52:754-61. https://doi.org/10.1016/j.ijantimicag.2018.08.016
Schwarz P, Bidaud AL, Dannaoui E. In vitro synergy of isavuconazole in combination with colistin against Candida auris. Sci Rep. 2020;10:1-8. https://doi.org/10.1038/s41598-020-78588-5
Eldesouky HE, Salama EA, Li X, Hazbun TR, Mayhoub AS, Seleem MN. Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species. Sci Rep. 2020;10:1-12. https://doi.org/10.1038/s41598-020-64571-7
Eldesouky HE, Salama EA, Hazbun TR, Mayhoub AS, Seleem MN. Ospemifene displays broad-spectrum synergistic interactions with itraconazole through potent interference with fungal efflux activities. Sci Rep. 2020;10:1-10. https://doi.org/10.1038/s41598-020-62976-y
Eldesouky HE, Lanman NA, Hazbun TR, Seleem MN. Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs. Virulence. 2020;11:1466-81. https://doi.org/10.1080/21505594.2020.1838741
Eldesouky HE, Salama EA, Lanman NA, Hazbun TR, Seleem MN. Potent synergistic interactions between lopinavir and azole antifungal drugs against emerging multidrug-resistant Candida auris. Antimicrob Agents Chemother. 2021;65:e00684-20. https://doi.org/10.1128/AAC.00684-20
Tan J, Jiang S, Tan L, Shi H, Yang L, Sun Y, et al. Antifungal activity of minocycline and azoles against fluconazole-resistant Candida species. Front Microbiol. 2021;12:649026. https://doi.org/10.3389/fmicb.2021.649026
Costa-de-Oliveira S, Miranda IM, Silva-Dias A, Silva AP, Rodrigues AG, Pina-Vaz C. Ibuprofen potentiates the in vivo antifungal activity of fluconazole against Candida albicans murine infection. Antimicrob Agents Chemother. 2015;59:4289-92. https://doi.org/10.1128/AAC.05056-14
Jin J, Guo N, Zhang J, Ding Y, Tang X, Liang J, et al. The synergy of honokiol and fluconazole against clinical isolates of azole-resistant Candida albicans. Lett Appl Microbiol. 2010;51:351-7. https://doi.org/10.1111/j.1472-765X.2010.02900.x
Hao W, Wang Y, Xi Y, Yang Z, Zhang H, Ge X. Activity of chlorhexidine acetate in combination with fluconazole against suspensions and biofilms of Candida auris. J Infect Chemother. 2022;28:29-34. https://doi.org/10.1016/j.jiac.2021.09.018
Lazzarini C, Haranahalli K, Rieger R, Ananthula HK, Desai PB, Ashbaugh A, et al. Acylhydrazones as antifungal agents targeting the synthesis of fungal sphingolipids. Antimicrob Agents Chemother. 2018;62:e00156-18. https://doi.org/10.1128/AAC.00156-18
Shaban S, Patel M, Ahmad A. Improved efficacy of antifungal drugs in combination with monoterpene phenols against Candida auris. Sci Rep. 2020;10:1162. https://doi.org/10.1038/s41598-020-58203-3