Overcomes Stress of Azole Drugs by Formation of Disomy in Specific Multiple Chromosomes

English version České info

Cryptococcus neoformans is a haploid environmental organism and the major cause of fungal meningoencephalitis in AIDS patients. Fluconazole (FLC), a triazole, is widely used for the maintenance therapy of cryptococcosis. Heteroresistance to FLC, an adaptive mode of azole resistance, was associated with FLC therapy failure cases but the mechanism underlying the resistance was unknown. We used comparative genome hybridization and quantitative real-time PCR in order to show that C. neoformans adapts to high concentrations of FLC by duplication of multiple chromosomes. Formation of disomic chromosomes in response to FLC stress was observed in both serotype A and D strains. Strains that adapted to FLC concentrations higher than their minimal inhibitory concentration (MIC) contained disomies of chromosome 1 and stepwise exposure to even higher drug concentrations induced additional duplications of several other specific chromosomes. The number of disomic chromosomes in each resistant strain directly correlated with the concentration of FLC tolerated by each strain. Upon removal of the drug pressure, strains that had adapted to high concentrations of FLC returned to their original level of susceptibility by initially losing the extra copy of chromosome 1 followed by loss of the extra copies of the remaining disomic chromosomes. The duplication of chromosome 1 was closely associated with two of its resident genes: ERG11, the target of FLC and AFR1, the major transporter of azoles in C. neoformans. This adaptive mechanism in C. neoformans may play an important role in FLC therapy failure of cryptococcosis leading to relapse during azole maintenance therapy.

Vyšlo v časopise: Overcomes Stress of Azole Drugs by Formation of Disomy in Specific Multiple Chromosomes. PLoS Pathog 6(4): e32767. doi:10.1371/journal.ppat.1000848
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000848

Souhrn

Zdroje

1. Kwon-ChungKJ

BennettJE

1992 Medical Mycology. Philadelphia Lea & Febiger 866

2. PerfectJR

CasadevallA

2002 Cryptococcosis. Infect Dis Clin North Am 16 837 874

3. ZoniosDI

BennettJE

2008 Update on azole antifungals. Semin Respir Crit Care Med 29 198 210

4. PerfectJR

CoxGM

1999 Drug resistance in Cryptococcus neoformans. Drug Resist Updat 2 259 269

5. KontoyiannisDP

SagarN

HirschiKD

1999 Overexpression of Erg11p by the regulatable GAL1 promoter confers fluconazole resistance in Saccharomyces cerevisiae. Antimicrob Agents Chemother 43 2798 2800

6. LampingE

MonkBC

NiimiK

HolmesAR

TsaoS

2007 Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryot Cell 6 1150 1165

7. AkinsRA

2005 An update on antifungal targets and mechanisms of resistance in Candida albicans. Med Mycol 43 285 318

8. BennettJE

IzumikawaK

MarrKA

2004 Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother 48 1773 1777

9. BrunS

BergesT

PoupardP

Vauzelle-MoreauC

RenierG

2004 Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob Agents Chemother 48 1788 1796

10. HelmerhorstEJ

VenuleoC

SanglardD

OppenheimFG

2006 Roles of cellular respiration, CgCDR1, and CgCDR2 in Candida glabrata resistance to histatin 5. Antimicrob Agents Chemother 50 1100 1103

11. SanglardD

OddsFC

2002 Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2 73 85

12. TsaiHF

KrolAA

SartiKE

BennettJE

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

13. WhiteTC

HollemanS

DyF

MirelsLF

StevensDA

2002 Resistance mechanisms in clinical isolates of Candida albicans. Antimicrob Agents Chemother 46 1704 1713

14. CowenLE

AndersonJB

KohnLM

2002 Evolution of drug resistance in Candida albicans. Annu Rev Microbiol 56 139 165

15. CowenLE

SteinbachWJ

2008 Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance. Eukaryot Cell 7 747 764

16. LupettiA

DanesiR

CampaM

Del TaccaM

KellyS

2002 Molecular basis of resistance to azole antifungals. Trends Mol Med 8 76 81

17. MarichalP

KoymansL

WillemsensS

BellensD

VerhasseltP

1999 Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology 145 2701 2713

18. SanglardD

IscherF

CalabreseD

MicheliM

BilleJ

1998 Multiple resistance mechanisms to azole antifungals in yeast clinical isolates. Drug Resist Updat 1 255 265

19. SelmeckiA

ForcheA

BermanJ

2006 Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313 367 370

20. SelmeckiA

Gerami-NejadM

PaulsonC

ForcheA

BermanJ

2008 An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1. Mol Microbiol 68 624 641

21. CowenLE

LindquistS

2005 Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309 2185 2189

22. CowenLE

CarpenterAE

MatangkasombutO

FinkGR

LindquistS

2006 Genetic architecture of Hsp90-dependent drug resistance. Eukaryot Cell 5 2184 2188

23. ArmengouA

PorcarC

MascaroJ

Garcia-BragadoF

1996 Possible development of resistance to fluconazole during suppressive therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 23 1337 1338

24. BergJ

ClancyCJ

NguyenMH

1998 The hidden danger of primary fluconazole prophylaxis for patients with AIDS. Clin Infect Dis 26 186 187

25. BirleyHD

JohnsonEM

McDonaldP

ParryC

CareyPB

1995 Azole drug resistance as a cause of clinical relapse in AIDS patients with cryptococcal meningitis. Int J STD AIDS 6 353 355

26. PaugamA

Dupouy-CametJ

BlancheP

GangneuxJP

Tourte-SchaeferC

1994 Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis. Clin Infect Dis 19 975 976

27. VenkateswarluK

TaylorM

ManningNJ

RinaldiMG

KellySL

1997 Fluconazole tolerance in clinical isolates of Cryptococcus neoformans. Antimicrob Agents Chemother 41 748 751

28. MondonP

PetterR

AmalfitanoG

LuzzatiR

ConciaE

1999 Heteroresistance to fluconazole and voriconazole in Cryptococcus neoformans. Antimicrob Agents Chemother 43 1856 1861

29. SionovE

ChangYC

GarraffoHM

Kwon-ChungKJ

2009 Heteroresistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence. Antimicrob Agents Chemother 53 2804 2815

30. PosteraroB

SanguinettiM

SanglardD

La SordaM

BocciaS

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

31. PolakovaS

BlumeC

ZarateJA

MentelM

Jorck-RambergD

2009 Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata. Proc Natl Acad Sci U S A 106 2688 2693

32. RustchenkoE

ShermanF

2002 Genetic instability of Candida albicans.

HowardDH

Fungi Pathogenic for Humans and Animals New York Marcel Dekker, Inc 723 776

33. HartwellLH

DutcherSK

WoodJS

GarvikB

1982 The fidelity of mitotic chromosome reproduction in S. cerevisiae. Rec Adv Yeast Mol Biol 1 28 38

34. RosenstrausMJ

ChasinLA

1978 Separation of linked markers in Chinese hamster cell hybrids: mitotic recombination is not involved. Genetics 90 735 760

35. TorresEM

SokolskyT

TuckerCM

ChanLY

BoselliM

2007 Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317 916 924

36. ZolanME

1995 Chromosome-length polymorphism in fungi. Microbiol Rev 59 686 698

37. VarmaA

Kwon-ChungKJ

1994 Formation of a minichromosome in Cryptococcus neoformans as a result of electroporative transformation. Curr Genet 26 54 61

38. KaernM

ElstonTC

BlakeWJ

CollinsJJ

2005 Stochasticity in gene expression: from theories to phenotypes. Nat Rev Genet 6 451 464

39. SternC

1958 The nucleus and somatic cell variation. J Cell Physiol Suppl52 1 27; discussion 27-34

40. KaferE

1976 Mitotic crossing over and nondisjunction in translocation heterozygotes of Aspergillus. Genetics 82 605 627

41. FernandezC

Lobo Md MdelV

Gomez-CoronadoD

LasuncionMA

2004 Cholesterol is essential for mitosis progression and its deficiency induces polyploid cell formation. Exp Cell Res 300 109 120

42. YamaguchiM

BiswasSK

OhkusuM

TakeoK

2009 Dynamics of the spindle pole body of the pathogenic yeast Cryptococcus neoformans examined by freeze-substitution electron microscopy. FEMS Microbiol Lett 296 257 265

43. GanemNJ

GodinhoSA

PellmanD

2009 A mechanism linking extra centrosomes to chromosomal instability. Nature 460 278 282

44. WapinskiI

PfefferA

FriedmanN

RegevA

2007 Natural history and evolutionary principles of gene duplication in fungi. Nature 449 54 61

45. RancatiG

PavelkaN

FlehartyB

NollA

TrimbleR

2008 Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell 135 879 893

46. TorelliR

PosteraroB

FerrariS

La SordaM

FaddaG

2008 The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol Microbiol 68 186 201

47. BicanicT

HarrisonT

NiepiekloA

DyakopuN

MeintjesG

2006 Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 43 1069 1073

48. FrieseG

DischerT

FussleR

SchmalreckA

LohmeyerJ

2001 Development of azole resistance during fluconazole maintenance therapy for AIDS-associated cryptococcal disease. AIDS 15 2344 2345

49. YamazumiT

PfallerMA

MesserSA

HoustonAK

BoykenL

2003 Characterization of heteroresistance to fluconazole among clinical isolates of Cryptococcus neoformans. J Clin Microbiol 41 267 272

50. CosteA

SelmeckiA

ForcheA

DiogoD

BougnouxME

2007 Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates. Eukaryot Cell 6 1889 1904

51. LeeH

BienCM

HughesAL

EspenshadePJ

Kwon-ChungKJ

2007 Cobalt chloride, a hypoxia-mimicking agent, targets sterol synthesis in the pathogenic fungus Cryptococcus neoformans. Mol Microbiol 65 1018 1033

52. ChangYC

Kwon-ChungKJ

1994 Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence. Mol Cell Biol 14 4912 4919

53. KavanaughLA

FraserJA

DietrichFS

2006 Recent evolution of the human pathogen Cryptococcus neoformans by intervarietal transfer of a 14-gene fragment. Mol Biol Evol 23 1879 1890