fungal drug resistance


Summary: The ability of fungi to resist or to become tolerant to chemotherapeutic agents, antifungal agents, or antibiotics. This resistance may be acquired through gene mutation.

Top Publications

  1. Huang S, Cao Y, Dai B, Sun X, Zhu Z, Cao Y, et al. In vitro synergism of fluconazole and baicalein against clinical isolates of Candida albicans resistant to fluconazole. Biol Pharm Bull. 2008;31:2234-6 pubmed
    ..This novel synergism of fluconazole and BE that can overcome drug-resistance in yeast may prove useful in combined treatment of fungal infections. ..
  2. Thompson G, Wiederhold N, Vallor A, Villareal N, Lewis J, Patterson T. Development of caspofungin resistance following prolonged therapy for invasive candidiasis secondary to Candida glabrata infection. Antimicrob Agents Chemother. 2008;52:3783-5 pubmed publisher
    ..Pre- and posttreatment isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed an F659V substitution within the FKS2 region of the glucan synthase complex. ..
  3. Singh S, Robbins N, Zaas A, Schell W, Perfect J, Cowen L. Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog. 2009;5:e1000532 pubmed publisher
    ..albicans, establish an entirely new role for Hsp90 in mediating resistance to echinocandins, and demonstrate that targeting Hsp90 provides a promising therapeutic strategy for the treatment of life-threatening fungal disease. ..
  4. Sellam A, Tebbji F, Nantel A. Role of Ndt80p in sterol metabolism regulation and azole resistance in Candida albicans. Eukaryot Cell. 2009;8:1174-83 pubmed publisher
    ..albicans. ..
  5. Sionov E, Chang Y, Garraffo H, Kwon Chung K. Heteroresistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence. Antimicrob Agents Chemother. 2009;53:2804-15 pubmed publisher
    ..Our study showed that heteroresistance to azole is universal and suggests that heteroresistance contributes to relapse of cryptococcosis during azole maintenance therapy. ..
  6. Garcia Effron G, Kontoyiannis D, Lewis R, Perlin D. Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies. Antimicrob Agents Chemother. 2008;52:4181-3 pubmed publisher
    ..Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1...
  7. Jansen G, Lee A, Epp E, Fredette A, Surprenant J, Harcus D, et al. Chemogenomic profiling predicts antifungal synergies. Mol Syst Biol. 2009;5:338 pubmed publisher
    ..Our method is therefore capable of accurately predicting compound synergy to aid the development of combinatorial antifungal therapies. ..
  8. Sanglard D, Coste A, Ferrari S. Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation. FEMS Yeast Res. 2009;9:1029-50 pubmed publisher
    ..Here, we review the current understanding of the transcriptional regulation of drug resistance genes from several fungal pathogens including Candida and Aspergillus species. ..
  9. van der Linden J, Jansen R, Bresters D, Visser C, Geerlings S, Kuijper E, et al. Azole-resistant central nervous system aspergillosis. Clin Infect Dis. 2009;48:1111-3 pubmed publisher
    ..Azole resistance significantly complicates the management of aspergillosis by delaying the initiation of adequate therapy and because effective alternative antifungal drugs are lacking...

More Information


  1. Cannon R, Lamping E, Holmes A, Niimi K, Baret P, Keniya M, et al. Efflux-mediated antifungal drug resistance. Clin Microbiol Rev. 2009;22:291-321, Table of Contents pubmed publisher
    ..Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps...
  2. Epp E, Vanier G, Harcus D, Lee A, Jansen G, Hallett M, et al. Reverse genetics in Candida albicans predicts ARF cycling is essential for drug resistance and virulence. PLoS Pathog. 2010;6:e1000753 pubmed publisher
    ..This work describes a new, widely conserved, broad-spectrum mechanism involved in fungal drug resistance and virulence and offers a potential route for single or improved combination therapies.
  3. Jia X, Wang Y, Jia Y, Gao P, Xu Y, Wang L, et al. RTA2 is involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in Candida albicans. Cell Mol Life Sci. 2009;66:122-34 pubmed publisher
    ..In conclusion, our findings suggest that RTA2 is involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in C. albicans. ..
  4. Sellam A, Askew C, Epp E, Lavoie H, Whiteway M, Nantel A. Genome-wide mapping of the coactivator Ada2p yields insight into the functional roles of SAGA/ADA complex in Candida albicans. Mol Biol Cell. 2009;20:2389-400 pubmed publisher
    ..Furthermore, ADA2 deletion causes a decrease in H3K9 acetylation levels of target genes, thus illustrating its importance for histone acetyl transferase activity. ..
  5. Peman J, Cantón E, Espinel Ingroff A. Antifungal drug resistance mechanisms. Expert Rev Anti Infect Ther. 2009;7:453-60 pubmed publisher
    ..Acquired resistance to flucytosine results from defects in its metabolism through enzymatic mutations, whereas resistance to amphotericin B may be mediated by increased catalase activity or defects in ergosterol biosynthesis. ..
  6. Garcia Effron G, Dilger A, Alcazar Fuoli L, Park S, Mellado E, Perlin D. Rapid detection of triazole antifungal resistance in Aspergillus fumigatus. J Clin Microbiol. 2008;46:1200-6 pubmed publisher
    ..fumigatus. When combined in a multiplex platform, the assay provides a comprehensive evaluation of drug resistance in A. fumigatus. ..
  7. 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 pubmed publisher
    ..Thus, the major mechanism by which i(5L) formation causes increased azole resistance is by amplifying two genes: ERG11 and TAC1...
  8. Cowen L, Steinbach W. Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance. Eukaryot Cell. 2008;7:747-64 pubmed publisher
  9. Cannon R, Lamping E, Holmes A, Niimi K, Tanabe K, Niimi M, et al. Candida albicans drug resistance another way to cope with stress. Microbiology. 2007;153:3211-7 pubmed
    ..albicans drug resistance from the perspective of it being a stress response and investigates how commonality with other stress-response pathways gives insights into the prospects for overcoming, or preventing, drug resistance. ..
  10. Lamping E, Monk B, Niimi K, Holmes A, Tsao S, Tanabe K, et al. Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryot Cell. 2007;6:1150-65 pubmed
    ..The modified hyperexpression system has wide application for the study of eukaryotic membrane proteins and could also be used in the pharmaceutical industry for drug screening. ..
  11. Jia X, Ma Z, Jia Y, Gao P, Zhang J, Wang Y, et al. RTA2, a novel gene involved in azole resistance in Candida albicans. Biochem Biophys Res Commun. 2008;373:631-6 pubmed publisher
    ..RTA2 expression was found elevated in clinical azole-resistant isolates of C. albicans. In conclusion, our findings suggest that RTA2 is involved in the development of azole resistance in C. albicans. ..
  12. Cowen L. The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat Rev Microbiol. 2008;6:187-98 pubmed publisher
    ..Harnessing Hsp90 holds great promise for treating life-threatening infectious diseases. ..
  13. Torelli R, Posteraro B, Ferrari S, La Sorda M, Fadda G, Sanglard D, et al. The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol Microbiol. 2008;68:186-201 pubmed publisher
    ..glabrata. The overlapping in function and regulation between CgSNQ2 and ScSNQ2 further highlight the relationship between S. cerevisiae and C. glabrata. ..
  14. Dunkel N, Liu T, Barker K, Homayouni R, Morschh user J, Rogers P. A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate. Eukaryot Cell. 2008;7:1180-90 pubmed publisher
    ..Here we show for the first time that a gain-of-function mutation in UPC2 leads to the increased expression of ERG11 and imparts resistance to fluconazole in clinical isolates of C. albicans...
  15. Znaidi S, De Deken X, Weber S, Rigby T, Nantel A, Raymond M. The zinc cluster transcription factor Tac1p regulates PDR16 expression in Candida albicans. Mol Microbiol. 2007;66:440-52 pubmed
    ..These results demonstrate that: (i) Tac1p controls PDR16 expression; (ii) Asn(972) to Asp(972) is a gain-of-function mutation; and (iii) Tac1p is positively autoregulated, directly or indirectly. ..
  16. Pfaller M, Boyken L, Hollis R, Kroeger J, Messer S, Tendolkar S, et al. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol. 2008;46:150-6 pubmed
    ..Our prospective sentinel surveillance reveals no evidence of emerging echinocandin resistance among invasive clinical isolates of Candida spp. ..
  17. Kanafani Z, Perfect J. Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis. 2008;46:120-8 pubmed publisher
  18. Gygax S, Vermitsky J, Chadwick S, Self M, Zimmerman J, Mordechai E, et al. Antifungal resistance of Candida glabrata vaginal isolates and development of a quantitative reverse transcription-PCR-based azole susceptibility assay. Antimicrob Agents Chemother. 2008;52:3424-6 pubmed publisher
    ..Resistance was defined as a >or=3-fold increase in CDR1 expression by this assay, which proved to be 100% sensitive and 95% specific in comparison to the gold standard broth microdilution assay. ..
  19. Borg von Zepelin M, Kunz L, Rüchel R, Reichard U, Weig M, Gross U. Epidemiology and antifungal susceptibilities of Candida spp. to six antifungal agents: results from a surveillance study on fungaemia in Germany from July 2004 to August 2005. J Antimicrob Chemother. 2007;60:424-8 pubmed
    ..This latest German survey of isolates from patients with fungaemia demonstrates a favourable situation with respect to antifungal susceptibilities for the antifungal substances tested. ..
  20. Garcia Effron G, Katiyar S, Park S, Edlind T, Perlin D. A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob Agents Chemother. 2008;52:2305-12 pubmed publisher
    ..Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype. ..
  21. Znaidi S, Weber S, Al Abdin O, Bomme P, Saidane S, Drouin S, et al. Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance. Eukaryot Cell. 2008;7:836-47 pubmed publisher
    ..They also suggest that Upc2p may contribute to azole resistance by regulating the expression of drug efflux pump-encoding genes in addition to ergosterol biosynthesis genes. ..
  22. Pasqualotto A, Denning D. New and emerging treatments for fungal infections. J Antimicrob Chemother. 2008;61 Suppl 1:i19-30 pubmed publisher
    ..Licensure and determination of their place in clinical practice requires randomized clinical studies, which are or will be underway. ..
  23. Xu Y, Chen L, Li C. Susceptibility of clinical isolates of Candida species to fluconazole and detection of Candida albicans ERG11 mutations. J Antimicrob Chemother. 2008;61:798-804 pubmed publisher
    ..In this survey, C. albicans is the major cause of candidiasis in non-AIDS patients, and some isolates that are resistant to fluconazole have G487T and T916C mutations in ERG11 that are associated with fluconazole resistance. ..
  24. Rodriguez Tudela J, Alcazar Fuoli L, Mellado E, Alastruey Izquierdo A, Monzon A, Cuenca Estrella M. Epidemiological cutoffs and cross-resistance to azole drugs in Aspergillus fumigatus. Antimicrob Agents Chemother. 2008;52:2468-72 pubmed publisher
    ..The results obtained in this study will help to develop clinical breakpoints for azole drugs and A. fumigatus. ..
  25. Rocha E, Garcia Effron G, Park S, Perlin D. A Ser678Pro substitution in Fks1p confers resistance to echinocandin drugs in Aspergillus fumigatus. Antimicrob Agents Chemother. 2007;51:4174-6 pubmed
    ..The equivalent mutation in Candida spp. has been implicated in echinocandin resistance. This work demonstrates that modification of Fks1p is a conserved mechanism for echinocandin resistance in pathogenic fungi. ..
  26. Goffeau A. Drug resistance: the fight against fungi. Nature. 2008;452:541-2 pubmed publisher
  27. Dannaoui E, Lortholary O, Raoux D, Bougnoux M, Galeazzi G, Lawrence C, et al. Comparative in vitro activities of caspofungin and micafungin, determined using the method of the European Committee on Antimicrobial Susceptibility Testing, against yeast isolates obtained in France in 2005-2006. Antimicrob Agents Chemother. 2008;52:778-81 pubmed
    ..A clear correlation was seen between the MICs for the two drugs. ..
  28. Cota J, Grabinski J, Talbert R, Burgess D, Rogers P, Edlind T, et al. Increases in SLT2 expression and chitin content are associated with incomplete killing of Candida glabrata by caspofungin. Antimicrob Agents Chemother. 2008;52:1144-6 pubmed
    ..In contrast, fungicidal activity and no chitin increase were observed in an isogenic Delta slt2 strain, suggesting a role for SLT2 and chitin production in the response of C. glabrata to caspofungin. ..
  29. Baixench M, Aoun N, Desnos Ollivier M, Garcia Hermoso D, Bretagne S, Ramires S, et al. Acquired resistance to echinocandins in Candida albicans: case report and review. J Antimicrob Chemother. 2007;59:1076-83 pubmed
    ..Our results indicate that is it useful to perform in vitro susceptibility testing in the cases of clinical failure during caspofungin therapy. ..
  30. Pfaller M, Messer S, Boyken L, Rice C, Tendolkar S, Hollis R, et al. In vitro survey of triazole cross-resistance among more than 700 clinical isolates of Aspergillus species. J Clin Microbiol. 2008;46:2568-72 pubmed publisher
    ..fumigatus and A. flavus) were strongest between VOR and RAV MICs and ITR and POS MICs. However, Aspergillus species for which MICs of VOR or POS were >2 microg/ml remain extremely rare (<1% of isolates). ..
  31. Chou H, Lo H, Chen K, Liao M, Li S. Multilocus sequence typing of Candida tropicalis shows clonal cluster enriched in isolates with resistance or trailing growth of fluconazole. Diagn Microbiol Infect Dis. 2007;58:427-33 pubmed
  32. Perlin D. Resistance to echinocandin-class antifungal drugs. Drug Resist Updat. 2007;10:121-30 pubmed
    ..and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom. ..
  33. Richardson M, Lass Florl C. Changing epidemiology of systemic fungal infections. Clin Microbiol Infect. 2008;14 Suppl 4:5-24 pubmed publisher
  34. Spreghini E, Maida C, Tomassetti S, Orlando F, Giannini D, Milici M, et al. Posaconazole against Candida glabrata isolates with various susceptibilities to fluconazole. Antimicrob Agents Chemother. 2008;52:1929-33 pubmed publisher
    ..glabrata. Additionally, the new triazole may be a therapeutic option in those cases where an FLC-resistant isolate is found to retain a relatively low POS MIC. ..
  35. Thakur J, Arthanari H, Yang F, Pan S, Fan X, Breger J, et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008;452:604-9 pubmed publisher
    ..This detailed mechanistic understanding of a fungal nuclear receptor-like gene regulatory pathway provides novel therapeutic targets for the treatment of multidrug-resistant fungal infections. ..
  36. Cleary J, Garcia Effron G, Chapman S, Perlin D. Reduced Candida glabrata susceptibility secondary to an FKS1 mutation developed during candidemia treatment. Antimicrob Agents Chemother. 2008;52:2263-5 pubmed publisher
    ..The initial isolate was susceptible, but isolates recovered during following relapses were not. All isolates were clonal, and high-MIC strains contained a mutation in the highly conserved hot spot 1 region of Fks1p. ..
  37. Pfaller M, Diekema D, Ostrosky Zeichner L, Rex J, Alexander B, Andes D, et al. Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J Clin Microbiol. 2008;46:2620-9 pubmed publisher
    ..Subsequently, the isolates should be submitted to a reference laboratory that will confirm the results by using a CLSI reference dilution method. ..
  38. Wang J, Li S, Yang Y, Chou H, Lo H. Association between fluconazole susceptibility and genetic relatedness among Candida tropicalis isolates in Taiwan. J Med Microbiol. 2007;56:650-3 pubmed
    ..Two distinct pulsotypes associated with fluconazole susceptibility were identified when these 23 resistant isolates, along with 13 susceptible ones, were analysed by PFGE. ..
  39. Coste A, Selmecki A, Forche A, Diogo D, Bougnoux M, d Enfert C, et al. Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates. Eukaryot Cell. 2007;6:1889-904 pubmed
    ..With the combination of these different modifications, sophisticated genotypes were obtained. The development of azole resistance in C. albicans is therefore a powerful instrument for generating genetic diversity...
  40. Pasquale T, Tomada J, Ghannoun M, DiPersio J, Bonilla H. Emergence of Candida tropicalis resistant to caspofungin. J Antimicrob Chemother. 2008;61:219 pubmed
  41. Coste A, Ramsdale M, Ischer F, Sanglard D. Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae. Microbiology. 2008;154:1491-501 pubmed publisher
    ..In conclusion, C. albicans possesses functional homologues of the S. cerevisiae Pdr1p and Pdr3p transcription factors; however, their properties in C. albicans have been rewired to other functions. ..
  42. Yang B, Peng M, Hou S, Sun J, Lee S, Lu J. Fluconazole-resistant Kodamaea ohmeri fungemia associated with cellulitis: case report and review of the literature. Int J Infect Dis. 2009;13:e493-7 pubmed publisher
    ..Fluconazole was replaced with amphotericin B deoxylate, and the fever and cellulitis inflammation gradually subsided. The patient was discharged in a stable condition. This is the first case of K. ohmeri fungemia in Taiwan. ..
  43. Obłąk E, Gamian A, Adamski R, Ułaszewski S. The physiological and morphological phenotype of a yeast mutant resistant to the quaternary ammonium salt N-(dodecyloxycarboxymethyl)-N,N,N-trimethyl ammonium chloride. Cell Mol Biol Lett. 2010;15:215-33 pubmed publisher
  44. Florent M, Noel T, Ruprich Robert G, da Silva B, Fitton Ouhabi V, Chastin C, et al. Nonsense and missense mutations in FCY2 and FCY1 genes are responsible for flucytosine resistance and flucytosine-fluconazole cross-resistance in clinical isolates of Candida lusitaniae. Antimicrob Agents Chemother. 2009;53:2982-90 pubmed publisher
    ..lusitaniae to support 5FC and 5FC/FLC resistance: either the nonsense mutation C505T in the fcy2 gene or the missense mutation T26C in the fcy1 gene. ..
  45. Martin Mazuelos E, Rodriguez Tudela J. [In vitro activity of anidulafungin. Comparison with the activity of other echinocandins]. Enferm Infecc Microbiol Clin. 2008;26 Suppl 14:7-13 pubmed
    ..or Mucorales spp. Data on the activity of this drug against other species are limited and do not allow conclusions to be drawn or recommendations to be made. Echinocandin resistance is uncommon and has little clinical relevance. ..
  46. Preveral S, Gayet L, Moldes C, Hoffmann J, Mounicou S, Gruet A, et al. A common highly conserved cadmium detoxification mechanism from bacteria to humans: heavy metal tolerance conferred by the ATP-binding cassette (ABC) transporter SpHMT1 requires glutathione but not metal-chelating phytochelatin peptides. J Biol Chem. 2009;284:4936-43 pubmed publisher
    ..Our results challenge the dogma of the two separate cadmium detoxification pathways and demonstrate that a common highly conserved mechanism has been selected during the evolution from bacteria to humans...
  47. Kano R, Itamoto K, Okuda M, Inokuma H, Hasegawa A, Balajee S. Isolation of Aspergillus udagawae from a fatal case of feline orbital aspergillosis. Mycoses. 2008;51:360-1 pubmed publisher
    ..Antifungal susceptibility testing results revealed that this isolate had high in vitro MIC to amphotericin B (AMB) that correlated with in vivo failure of therapy with AMB. ..
  48. Hoehamer C, Cummings E, Hilliard G, Rogers P. Changes in the proteome of Candida albicans in response to azole, polyene, and echinocandin antifungal agents. Antimicrob Agents Chemother. 2010;54:1655-64 pubmed publisher
    ..Some of these antifungal-responsive proteins may represent potential targets for the development of novel therapeutics that could enhance the antifungal activities of these drugs. ..
  49. García López M, Mirón García M, Garrido Godino A, Mingorance C, Navarro F. Overexpression of SNG1 causes 6-azauracil resistance in Saccharomyces cerevisiae. Curr Genet. 2010;56:251-63 pubmed publisher
    ..Taken together, these results show new mechanisms involved in the resistance and susceptibility to 6AU. ..
  50. Mang T, Mikulski L, Hall R. Photodynamic inactivation of normal and antifungal resistant Candida species. Photodiagnosis Photodyn Ther. 2010;7:98-105 pubmed publisher
    ..Further Candida isolates from AIDS patients that had demonstrated fluconazole and amphotericin B resistance were equally susceptible to photodynamic killing. ..
  51. Zhou X, Arita A, Ellen T, Liu X, Bai J, Rooney J, et al. A genome-wide screen in Saccharomyces cerevisiae reveals pathways affected by arsenic toxicity. Genomics. 2009;94:294-307 pubmed publisher
    ..Our studies have potential implications for understanding toxicity and carcinogenesis in arsenic-induced human conditions, such as cancer and aging. ..
  52. Wei C, Katoh H, Nishimura K, Ishii H. Site-directed mutagenesis of the cytochrome b gene and development of diagnostic methods for identifying QoI resistance of rice blast fungus. Pest Manag Sci. 2009;65:1344-51 pubmed publisher
    ..Mutation of the cytochrome b gene of rice blast fungus would be specifically detected from diseased leaves and seeds using the molecular methods developed in this study. ..
  53. Chen C, Zhou L, Bi C, Li H, Wang J, Zhou M. [Resistant mechanism of Fusarium graminearum against carbendazim, unrelative to alpha2-tubulin gene]. Wei Sheng Wu Xue Bao. 2008;48:1356-61 pubmed
    ..The resistance of F. graminearum against carbendazim was irrelative to the nucleotide sequence of alpha2-tubulin. ..