Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci.
Chromosomes, Fungal
/ genetics
Clone Cells
Cryptococcus
/ drug effects
Drug Resistance, Fungal
/ drug effects
Flucytosine
/ pharmacology
Fungal Proteins
/ genetics
Gene Dosage
Gene Duplication
Gene Expression Regulation, Fungal
/ drug effects
Genes, Suppressor
Genetic Variation
Genome, Fungal
Intracellular Space
/ metabolism
Microbial Sensitivity Tests
Mutation
/ genetics
Reproducibility of Results
Uridine Diphosphate Glucuronic Acid
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 06 2021
08 06 2021
Historique:
received:
19
01
2021
accepted:
14
05
2021
entrez:
9
6
2021
pubmed:
10
6
2021
medline:
16
6
2021
Statut:
epublish
Résumé
The antifungal agent 5-fluorocytosine (5-FC) is used for the treatment of several mycoses, but is unsuitable for monotherapy due to the rapid development of resistance. Here, we show that cryptococci develop resistance to 5-FC at a high frequency when exposed to concentrations several fold above the minimal inhibitory concentration. The genomes of resistant clones contain alterations in genes relevant as well as irrelevant for 5-FC resistance, suggesting that 5-FC may be mutagenic at moderate concentrations. Mutations in FCY2 (encoding a known permease for 5-FC uptake), FCY1, FUR1, UXS1 (encoding an enzyme that converts UDP-glucuronic acid to UDP-xylose) and URA6 contribute to 5-FC resistance. The uxs1 mutants accumulate UDP-glucuronic acid, which appears to down-regulate expression of permease FCY2 and reduce cellular uptake of the drug. Additional mutations in genes known to be required for UDP-glucuronic acid synthesis (UGD1) or a transcriptional factor NRG1 suppress UDP-glucuronic acid accumulation and 5-FC resistance in the uxs1 mutants.
Identifiants
pubmed: 34103502
doi: 10.1038/s41467-021-23745-1
pii: 10.1038/s41467-021-23745-1
pmc: PMC8187385
doi:
Substances chimiques
Fungal Proteins
0
Uridine Diphosphate Glucuronic Acid
2616-64-0
Flucytosine
D83282DT06
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3418Références
Eukaryot Cell. 2006 Jul;5(7):1147-56
pubmed: 16835458
Biochemistry. 1968 May;7(5):1761-70
pubmed: 4297054
mBio. 2018 Dec 4;9(6):
pubmed: 30514783
Genome Res. 2016 Oct;26(10):1355-1362
pubmed: 27440870
Mol Microbiol. 2002 Aug;45(3):837-49
pubmed: 12139628
Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14607-12
pubmed: 11717398
PLoS Genet. 2014 Apr 17;10(4):e1004261
pubmed: 24743168
Clin Infect Dis. 2014 May;58(9):1308-11
pubmed: 24585567
Rev Iberoam Micol. 2008 Jun;25(2):101-6
pubmed: 18473504
J Virol. 2012 Sep;86(18):9640-6
pubmed: 22740415
mBio. 2019 Aug 27;10(4):
pubmed: 31455652
Nature. 1959 Oct 17;184:1213-5
pubmed: 14403183
Med Mycol. 2018 Oct 1;56(7):857-867
pubmed: 29554336
Crit Rev Microbiol. 1987;15(1):45-56
pubmed: 3319420
Nat Commun. 2020 Jan 8;11(1):127
pubmed: 31913284
Eur J Biochem. 1973 Jan 15;32(2):276-82
pubmed: 4569075
Yeast. 2006 Jul 15;23(9):707-15
pubmed: 16845689
Am J Med. 1987 Aug;83(2):236-42
pubmed: 3303926
Antimicrob Agents Chemother. 2018 May 25;62(6):
pubmed: 29610197
FEMS Yeast Res. 2016 May;16(3):
pubmed: 26945893
mBio. 2011 Feb 08;2(1):e00342-10
pubmed: 21304167
Clin Microbiol Rev. 1999 Oct;12(4):501-17
pubmed: 10515900
Antimicrob Agents Chemother. 2010 Jun;54(6):2303-11
pubmed: 20385871
Science. 2006 Jul 21;313(5785):367-70
pubmed: 16857942
Annu Rev Microbiol. 1998;52:591-625
pubmed: 9891809
Antimicrob Agents Chemother. 2004 Nov;48(11):4377-86
pubmed: 15504867
Antimicrob Agents Chemother. 1999 Aug;43(8):1856-61
pubmed: 10428902
Clin Infect Dis. 2010 Feb 1;50(3):291-322
pubmed: 20047480
J Biol Chem. 2004 Dec 3;279(49):51669-76
pubmed: 15383535
Biochemistry. 1966 May;5(5):1625-32
pubmed: 5335810
Infect Immun. 2003 Sep;71(9):4831-41
pubmed: 12933823
Nature. 1956 Sep 8;178(4532):531-2
pubmed: 13358789
PLoS Comput Biol. 2016 Apr 21;12(4):e1004873
pubmed: 27100738
Antimicrob Agents Chemother. 2010 Nov;54(11):4733-8
pubmed: 20823283
PLoS One. 2015 Aug 12;10(8):e0135110
pubmed: 26267134
Cold Spring Harb Perspect Med. 2014 Jul 01;4(7):a019760
pubmed: 24985132
Eukaryot Cell. 2004 Dec;3(6):1601-8
pubmed: 15590833
Nucleic Acids Res. 2012 Jan;40(Database issue):D675-81
pubmed: 22064857
J Clin Invest. 2019 Mar 1;129(3):999-1014
pubmed: 30688656
Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4601-5
pubmed: 2052544
Biotechniques. 1993 Apr;14(4):538-40
pubmed: 8476589
Antimicrob Agents Chemother. 1983 Jan;23(1):79-85
pubmed: 6338821
Antimicrob Agents Chemother. 2018 Mar 27;62(4):
pubmed: 29378705
Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12003-8
pubmed: 11593010
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17258-63
pubmed: 15572442
Metabolites. 2020 Mar 12;10(3):
pubmed: 32178468
PLoS Pathog. 2010 Apr 01;6(4):e1000848
pubmed: 20368972
Mol Gen Genet. 1986 Oct;205(1):74-81
pubmed: 3025561
Antimicrob Agents Chemother. 2007 Jan;51(1):369-71
pubmed: 17060521
J Mol Biol. 1969 Sep 14;44(2):363-75
pubmed: 4940922
Clin Infect Dis. 1998 Aug;27(2):260-4
pubmed: 9709874
Genome Biol. 2006;7(10):R100
pubmed: 17076895
Antimicrob Agents Chemother. 1973 Jun;3(6):649-56
pubmed: 4597734