Emergence and Evolution of Antifungal Resistance

Thomas D. Edlind

doi:10.1128/9781555815639.ch25

Chapter 25 : Emergence and Evolution of Antifungal Resistance

Author: Thomas D. Edlind¹

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Drexel University College of Medicine, Philadelphia, PA 19129

Content Type: Monograph

Publication Year: 2008

Category: Fungi and Fungal Pathogenesis; Bacterial Pathogenesis

Book DOI: 10.1128/9781555815639

Chapter DOI: 10.1128/9781555815639.ch25

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Emergence and Evolution of Antifungal Resistance, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815639/9781555814144_Chap25-1.gif /docserver/preview/fulltext/10.1128/9781555815639/9781555814144_Chap25-2.gif

Abstract:

The intent of this chapter is to take a broader perspective, extending our understanding of acquired resistance in a few fungi to the problem of intrinsic (primary) resistance throughout the fungal kingdom. In diploid fungi heterozygous mutations associated with antifungal resistance may be dominant or recessive; under selective pressure the latter may undergo mitotic gene conversion to homozygosity. A role for genome instability (chromosome rearrangements or aneuploidy) in antifungal resistance was illustrated by recent studies of Candida albicans. The first generation of azole antifungals were imidazoles such as clotrimazole and miconazole. As with PDR1, TAC1 is evolutionarily divergent, and there are no unambiguous orthologs outside of the C. albicans-containing CTG clade. The first generation of research on antifungal resistance has focused on understanding the basis for acquired resistance in the experimentally tractable fungi Saccharomyces cerevisiae, C. albicans, and C. glabrata. The second generation of antifungal resistance research will explore the basis for intrinsic resistance in the diverse fungal pathogens that increasingly threaten immunocompromised patients, particularly Aspergillus, Fusarium, Scedosporium, and zygomycete species. Ultimately, understanding the molecular basis for intrinsic antifungal resistance will facilitate the design of second-generation inhibitors with an extended spectrum of activity.

Citation: Edlind T. 2008. Emergence and Evolution of Antifungal Resistance, p 297-306. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch25

Highlighted Text: Show | Hide

Full text loading...

Figures

Emergence and Evolution of Antifungal Resistance

[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815639.ch25-1,webId=/content/author/10.1128/9781555815639.ch25-1,properties={foaf_givenname=Thomas D., foaf_name=Thomas D. Edlind, foaf_surname=Edlind, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815639.ch25-aff1]]}]]

/content/10.1128/9781555815639.ch25.ch25fig01

Figure 1.

The ergosterol biosynthesis pathway, in abbreviated form. Each arrow represents an enzymatic step. Genes encoding enzymes specifically targeted by antifungals are indicated. The pathway was deduced in S. cerevisiae (Lees et al., 1995) but appears to be valid for other fungi.

10.1128/9781555815639/f0298-01_thmb.gif

10.1128/9781555815639/f0298-01.gif

Figure 1.

/content/10.1128/9781555815639.ch25.ch25fig02

Figure 2.

Alignment of Fks sequences encompassing the two hot spots for echinocandin resistance. Ca, C. albicans; Sc, S. cerevisiae; Fs, F. solani; Cn, C. neoformans; Ro, R. oryzae. Residues involved in acquired resistance are indicated (bold underline), as are positions predicted to play a role in intrinsic resistance (▲). All sequences represent Fks1, except R. oryzae Fks, which are arbitrarily numbered.

10.1128/9781555815639/f0300-01_thmb.gif

10.1128/9781555815639/f0300-01.gif

Figure 2.

/content/10.1128/9781555815639.ch25.ch25fig03

Figure 3.

Alignment of partial Erg11/Cyp51 sequences from C. albicans (Ca), C. krusei (Ck), F. verticillioides (FvA, FvB), R. oryzae (RoA, RoB), and A. fumigatus (AfA, AfB). C. albicans Erg11 and A. fumigatus Cyp51A residues associated with acquired azole resistance are indicated (bold underline), with mutations listed above or below the wild-type sequence. Residues in the Ck, Fv, and Ro sequences that align with these mutations and are postulated to play a role in intrinsic azole resistance are also indicated (bold underline). Fv and Ro residue numbers are shown in parentheses since the true start sites were not identified.

10.1128/9781555815639/f0302-01_thmb.gif

10.1128/9781555815639/f0302-01.gif

Figure 3.

/content/10.1128/9781555815639.ch25.ch25fig04

Figure 4.

Anatomy and evolution of the Pdr1 family of transcriptional regulators of azole and multidrug resistance. Sc, S. cerevisiae; Cg, C. glabrata. Bars indicate approximate locations of the DNA-binding, inhibitory, and activation domains. Underlined C. glabrata residues are conserved in either S. cerevisiae Pdr1 or Pdr3. Gain-of-function mutations are shown above or below the S. cerevisiae Pdr1 or Pdr3 sequences, respectively. Mutations associated with azole-resistance in C. glabrata Pdr1 are indicated (▲).

10.1128/9781555815639/f0303-01_thmb.gif

10.1128/9781555815639/f0303-01.gif

Figure 4.

References

/content/book/10.1128/9781555815639.ch25

1. Akins, R. A. 2005. An update on antifungal targets and mechanisms of resistance in Candida albicans. Med. Mycol. 43: 285– 318.

2. Balashov, S. V.,, S. Park, and, D. S. Perlin. 2006. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob. Agents Chemother. 50: 2058– 2063.

3. Baldauf, S. L., and, J. D. Palmer. 1993. Animals and fungi are each other’s closest relatives: congruent evidence from multiple proteins. Proc. Natl. Acad. Sci. USA 90: 11558– 11562.

4. Balzi, E., and, A. Goffeau. 1995. Yeast multidrug resistance: the PDR network. J. Bioenerg. Biomembr. 27: 71– 76.

5. Beggs, W. H. 1992. Direct membrane damage and miconazole lethality. Res. Commun. Chem. Pathol. Pharmacol. 77: 249– 252.

6. Carvajal, E.,, H. B. van den Hazel,, A. Cybularz-Kolaczkowska,, A. Balzi, and, A. Goffeau. 1997. Molecular and phenotypic characterization of yeast PDR1 mutants that show hyperactive transcription of various ABC multidrug transporter genes. Mol. Gen. Genet. 256: 406– 415.

7. Chau, A. S.,, G. Chen,, P. M. McNicholas, and, P. A Mann. 2006. Molecular basis for enhanced activity of posaconazole against Absidia corymbifera and Rhizopus oryzae. Antimicrob. Agents Chemother. 50: 3917– 3919.

8. Coste, A.,, V. Turner,, F. Ischer,, J. Morschhauser,, A. Forche,, A. Selmecki,, J. Berman,, J. Bille, and, D. Sanglard. 2006. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 172: 2139– 2156.

9. Coste, A. T.,, M. Karababa,, F. Ischer,, J. Bille, and, D. Sanglard. 2004. 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 3: 1639– 1652.

10. Cuenca-Estrella, M.,, A. Gomez-Lopez,, E. Mellado,, M. J. Buitrago,, A. Monzon, and, J. L. Rodriguez-Tudela. 2006. Head-to-head comparison of the activities of currently available antifungal agents against 3,378 Spanish clinical isolates of yeasts and filamentous fungi. Antimicrob. Agents Chemother. 50: 917– 921.

11. DeRisi, J.,, B. van den Hazel,, P. Marc,, E. Balzi,, P. Brown,, C. Jacq, and, A. Goffeau. 2000. Genome microarray analysis of transcriptional activation in multidrug resistance yeast mutants. FEBS Lett. 470: 156– 160.

12. Dodgson, A. R.,, K. J. Dodgson,, C. Pujol,, M. A. Pfaller, and, D. R. Soll. 2004. Clade-specific flucytosine resistance is due to a single nucleotide change in the FUR1 gene of Candida albicans. Antimicrob. Agents Chemother. 48: 2223– 2227.

13. Douglas, C. M. 2001. Fungal β(1,3)- D-glucan synthesis. Med. Mycol. 39 (Suppl 1): 55– 66.

14. Ellis, D. 2000. Amphotericin B: spectrum and resistance. J. Antimicrob. Chemother. 49 (Suppl 1): 7– 10.

15. Espinel-Ingroff, A. 2003. In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature. Rev. Iberoam. Micol. 20: 121– 136.

16. Fitzpatrick, D. A.,, M. E. Logue,, J. E. Stajich,, G. Butler. 2006. A fungal phylogeny based on 42 complete genomes derived from supertree and combined gene analysis. BMC Evol. Biol. 6: 99.

17. Fukuoka, T.,, D. A. Johnston,, C. A. Winslow,, M. J. de Groot,, C. Burt,, A. Hitchcock, and, S. G. Filler. 2003. Genetic basis for differential activities of fluconazole and voriconazole against Candida krusei. Antimicrob. Agents Chemother. 47: 1213– 1219.

18. Geber, A.,, C. A. Hitchcock,, J. E. Swartz,, F. S. Pullen,, K. E. Marsden,, K. J. Kwon-Chung, and, J. E. Bennett. 1995. Deletion of the Candida glabrata ERG3 and ERG11 genes: effect on cell viability, cell growth, sterol composition, and antifungal susceptibility. Antimicrob. Agents Chemother. 39: 2708– 2717.

19. Groll, A. H., and, T. J. Walsh. 2001. Uncommon opportunistic fungi: new nosocomial threats. Clin. Microbiol. Infect. 7 (Suppl 2): 8– 24.

20. Hope, W. W.,, L. Tabernero,, D. W. Denning, and, M. J. Anderson. 2004. Molecular mechanisms of primary resistance to flucytosine in Candida albicans. Antimicrob. Agents Chemother. 48: 4377– 4386.

21. Howard, S. J.,, I. Webster,, C. B. Moore,, R. E. Gardiner,, S. Park,, D. S. Perlin, and, D. W. Denning. 2006. Multi-azole resistance in Aspergillus fumigatus. Int. J. Antimicrob. Agents 28: 450– 453.

22. Kaneshiro, E. S. 2004. Sterol metabolism in the opportunistic pathogen Pneumocystis: advances and new insights. Lipids 39: 753– 761.

23. Katiyar, S.,, M. Pfaller, and, T. Edlind. 2006. Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility. Antimicrob. Agents Chemother. 50: 2892– 2894.

24. Kelly, S. L.,, D. C. Lamb,, A. J. Corran,, B. C. Baldwin, and, D. E. Kelly. 1995. Mode of action and resistance to azole antifungals associated with the formation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol. Biochem. Biophys. Res. Commun. 207: 910– 915.

25. Kern, L.,, J. de Montigny,, F. Lacroute, and, R. Jund. 1991. Regulation of the pyrimidine salvage pathway by the FUR1 gene product of Saccharomyces cerevisiae. Curr. Genet. 19: 333– 337.

26. Kondoh, O.,, T. Takasuka,, M. Arisawa,, Y. Aoki, and, T. Watanabe. 2000. Differential sensitivity between Fks1p and Fks2p against a novel β-1,3-glucan synthase inhibitor, aerothricin3. J. Biol. Chem. 277: 41744– 41749.

27. Lamb, D. C.,, D. E. Kelly,, B. C. Baldwin, and, S. L. Kelly. 2000. Differential inhibition of human CYP3A4 and Candida albicans CYP51 with azole antifungal agents. Chem. Biol. Interact. 125: 165– 175.

28. Laverdiere, M.,, R. G. Lalonde,, J. G. Baril,, D. C. Sheppard,, S. Park, and, D. S. Perlin. 2006. Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis. J. Antimicrob. Chemother. 57: 705– 708.

29. Lees, N. D.,, Skaggs, B.,, D. R. Kirsch, and, M. Bard. 1995. Cloning of the late genes in the ergosterol biosynthetic pathway of Saccharomyces cerevisiae—a review. Lipids 30: 221– 226.

30. Leppert, G.,, R. McDevitt,, S. C. Falco,, T. K. Van Dyk,, M. B. Ficke, and, J. Golin. 1990. Cloning by gene amplification of two loci conferring multiple drug resistance in Saccharomyces. Genetics 125: 13– 20.

31. Liu, M.,, M. D. Healy,, B. A. Dougherty,, K. M. Esposito,, T. C. Maurice,, C. E. Mazzucco,, R. E. Bruccoleri,, D. B. Davison,, M. Frosco,, J. F. Barrett, and, Y. K. Wang. 2006. Conserved fungal genes as potential targets for broad-spectrum antifungal drug discovery. Eukaryot. Cell 5: 638– 649.

32. Lupetti, A.,, R. Danesi,, M. Campa,, M. Del Tacca, and, S. Kelly. 2002. Molecular basis of resistance to azole antifungals. Trends. Mol. Med. 8: 76– 81.

33. Maebashi, K.,, M. Kudoh,, Y. Nishiyama,, K. Makimura,, Y. Kamai,, K. Uchida, and, H. Yamaguchi. 2003. Proliferation of intracellular structure corresponding to reduced affinity of fluconazole for cytochrome P-450 in two low-susceptibility strains of Candida albicans isolated from a Japanese AIDS patient. Microbiol. Immunol. 47: 117– 124.

34. Marichal, P.,, L. Koymans,, S. Willemsens,, D. Bellens,, P. Verhasselt,, W. Luyten,, M. Borgers,, F. C. Ramaekers,, F. C. Odds, and, H. V. Bossche. 1999. Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology 145: 2701– 2713.

35. Mellado, E.,, L. Alcazar-Fuoli,, G. Garcia-Effron,, A. Alastruey-Izquierdo,, M. Cuenca-Estrella, and, J. L. Rodriguez-Tudela. 2006. New resistance mechanisms to azole drugs in Aspergillus fumigatus and emergence of antifungal drugs-resistant A. fumigatus atypical strains. Med. Mycol. 44 (Suppl): 367– 371.

36. Messer, S. A.,, R. N. Jones, and, T. R. Fritsche. 2006. International surveillance of Candida spp. and Aspergillus spp.: report from the SENTRY Antimicrobial Surveillance Program (2003). J. Clin. Microbiol. 44: 1782– 1787.

37. Miyazaki, H.,, Y. Miyazaki,, A. Geber,, T. Parkinson,, C. Hitchcock,, D. J. Falconer,, D. J. Ward,, K. Marsden, and, J. E. Bennett. 1998. Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata. Antimicrob. Agents Chemother. 42: 1695– 1701.

38. Morschhauser, J. 2002. The genetic basis of fluconazole resistance development in Candida albicans. Biochim. Biophys. Acta 1587: 240– 248.

39. Ohyama, T.,, S. Miyakoshi, and, F. Isono. 2004. FKS1 mutations responsible for selective resistance of Saccharomyces cerevisiae to the novel 1,3-β-glucan synthase inhibitor arborcandin C. Antimicrob. Agents Chemother. 48: 319– 322.

40. Park, S.,, R. Kelly,, J. N. Kahn,, J. Robles,, M. J. Hsu,, E. Register,, W. Li,, V. Vyas,, H. Fan,, G. Abruzzo,, A. Flattery,, C. Gill,, G. Chrebet,, S. A. Parent,, M. Kurtz,, H. Teppler,, C. M. Douglas, and, D. S. Perlin. 2005. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob. Agents Chemother. 49: 3264– 3273.

41. Perea, S.,, J. L. Lopez-Ribot,, W. R. Kirkpatrick,, R. K. McAtee,, R. A. Santillan,, M. Martinez,, D. Calabrese,, D. Sanglard, and, T. F. Patterson. 2001. Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 45: 2676– 2684.

42. Pfaller, M. A., and, D. J. Diekema. 2004. Rare and emerging opportunistic fungal pathogens: concern for resistance beyond Candida albicans and Aspergillus fumigatus. J. Clin. Microbiol. 42: 4419– 4431.

43. Podust, L. M.,, T. L. Poulos, and, M. R. Waterman. 2001. Crystal structure of cytochrome P450 14alpha-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc. Natl. Acad. Sci. USA 98: 3068– 3073.

44. Prasad, R.,, P. De Wergifosse,, A. Goffeau, and, E. Balzi. 1995. Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals. Curr. Genet. 27: 320– 329.

45. Roemer, T.,, B. Jiang,, J. Davison,, T. Ketela,, K. Veillette,, A. Breton,, F. Tandia,, A. Linteau,, S. Sillaots,, C. Marta,, N. Martel,, S. Veronneau,, S. Lemieux,, S. Kauffman,, J. Becker,, R. Storms,, C. Boone, and, H. Bussey. 2003. Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol. Microbiol. 50: 167– 181.

46. Sanglard, D.,, F. Ischer,, D. Calabrese,, P. A. Majcherczyk, and, J. Bille. 1999. The ATP binding cassette transporter gene CgCDR1 from Candida glabrata is involved in the resistance of clinical isolates to azole antifungal agents. Antimicrob. Agents Chemother. 43: 2753– 2765.

47. Sanglard, D.,, F. Ischer,, M. Monod, and, J. Bille. 1996. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob. Agents Chemother. 40: 2300– 2305.

48. Sanglard, D.,, F. Ischer,, T. Parkinson,, D. Falconer, and, J. Bille. 2003. Candida albicans mutations in the ergosterol biosynthetic pathway and resistance to several antifungal agents. Antimicrob. Agents Chemother. 47: 2404– 2412.

49. Sanglard, D.,, K. Kuchler,, F. Ischer,, J. L. Pagani,, M. Monod, and, J. Bille. 1995. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob. Agents Chemother. 39: 2378– 2386.

50. Sanglard, D., and, F. C. Odds. 2002. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect. Dis. 2: 73– 85.

51. Selmecki, A.,, A. Forche, and, J. Berman. 2006. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313: 367– 370.

52. Smith, W. L., and, T. D. Edlind. 2002. Histone deacetylase inhibitors enhance Candida albicans sensitivity to azoles and related antifungals: correlation with reduction in CDR and ERG upregulation. Antimicrob. Agents Chemother. 46: 3532– 3539.

53. Talibi, D., and, M. Raymond. 1999. Isolation of a putative Candida albicans transcriptional regulator involved in pleiotropic drug resistance by functional complementation of a pdr1 pdr3 mutation in Saccharomyces cerevisiae. J. Bacteriol. 181: 231– 240.

54. Tsai, H. F.,, A. A. Krol,, K. E. Sarti, and, J. E. Bennett. 2006. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob. Agents Chemother. 50: 1384– 1392.

55. Vermitsky, J. P.,, K. D. Earhart,, W. L. Smith,, R. Homayouni,, T. D. Edlind, and, P. D. Rogers. 2006. Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol. Microbiol. 61: 704– 722.

56. Vermitsky, J. P., and, T. D. Edlind. 2004. Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob. Agents Chemother. 48: 3773– 3781.

57. Whelan, W. L. 1987. The genetic basis of resistance to 5-fluorocytosine in Candida species and Cryptococcus neoformans. Crit. Rev. Microbiol. 15: 45– 56.

58. White, T. C.,, S. Holleman,, F. Dy,, L. F. Mirels, and, D. A. Stevens. 2002. Resistance mechanisms in clinical isolates of Candida albicans. Antimicrob. Agents Chemother. 46: 1704– 1713.

59. White, T. C.,, K. A. Marr, and, R. A. Bowden. 1998. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin. Microbiol. Rev. 11: 382– 402.

60. Xiao, L.,, V. Madison,, A. S. Chau,, D. Loebenberg,, R. E. Palermo, and, P. M. McNicholas. 2004. Three-dimensional models of wild-type and mutated forms of cytochrome P450 14α-sterol demethylases from Aspergillus fumigatus and Candida albicans provide insights into posaconazole binding. Antimicrob. Agents Chemother. 48: 568– 574.