CRISPR-Cas9 approach confirms Calcineurin-responsive zinc finger 1 (Crz1) transcription factor as a promising therapeutic target in echinocandin-resistant Candida glabrata.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2022
2022
Historique:
received:
24
10
2021
accepted:
07
03
2022
entrez:
18
3
2022
pubmed:
19
3
2022
medline:
6
5
2022
Statut:
epublish
Résumé
Invasive fungal infections, which kill more than 1.6 million patients each year worldwide, are difficult to treat due to the limited number of antifungal drugs (azoles, echinocandins, and polyenes) and the emergence of antifungal resistance. The transcription factor Crz1, a key regulator of cellular stress responses and virulence, is an attractive therapeutic target because this protein is absent in human cells. Here, we used a CRISPR-Cas9 approach to generate isogenic crz1Δ strains in two clinical isolates of caspofungin-resistant C. glabrata to analyze the role of this transcription factor in susceptibility to echinocandins, stress tolerance, biofilm formation, and pathogenicity in both non-vertebrate (Galleria mellonella) and vertebrate (mice) models of candidiasis. In these clinical isolates, CRZ1 disruption restores the susceptibility to echinocandins in both in vitro and in vivo models, and affects their oxidative stress response, biofilm formation, cell size, and pathogenicity. These results strongly suggest that Crz1 inhibitors may play an important role in the development of novel therapeutic agents against fungal infections considering the emergence of antifungal resistance and the low number of available antifungal drugs.
Identifiants
pubmed: 35303047
doi: 10.1371/journal.pone.0265777
pii: PONE-D-21-33405
pmc: PMC8932611
doi:
Substances chimiques
Antifungal Agents
0
Echinocandins
0
Transcription Factors
0
Calcineurin
EC 3.1.3.16
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0265777Déclaration de conflit d'intérêts
P.L.P received grants from Astellas, Basilea, MSD and Pfizer and speaker’s fees from Gilead, Basilea, Pfizer and MSD. The other authors declare not have any conflict of interest to disclose.
Références
Sci Rep. 2016 Oct 21;6:35766
pubmed: 27767081
PLoS Pathog. 2009 Jul;5(7):e1000532
pubmed: 19649312
J Bacteriol. 1997 Apr;179(7):2331-8
pubmed: 9079920
Virulence. 2017 Feb 17;8(2):186-197
pubmed: 27325145
mSphere. 2018 Apr 25;3(2):
pubmed: 29695624
Mol Microbiol. 2019 Jan;111(1):6-16
pubmed: 30299574
Eukaryot Cell. 2005 Apr;4(4):703-15
pubmed: 15821130
Antimicrob Agents Chemother. 2010 Dec;54(12):5042-7
pubmed: 20837754
PLoS Pathog. 2015 Jul 16;11(7):e1004936
pubmed: 26181382
Fungal Biol Rev. 2014 Oct;28(2-3):56-69
pubmed: 25383089
Clin Microbiol Infect. 2016 Jan;22(1):87-93
pubmed: 26432192
G3 (Bethesda). 2012 Jun;2(6):675-91
pubmed: 22690377
Microbiol Mol Biol Rev. 2011 Jun;75(2):213-67
pubmed: 21646428
Methods Mol Biol. 2012;845:469-85
pubmed: 22328396
Nat Rev Drug Discov. 2017 Feb;16(2):89-100
pubmed: 28008168
Future Microbiol. 2019 Sep;14:1243-1255
pubmed: 31625446
Mol Cell. 2014 Aug 7;55(3):422-435
pubmed: 24930733
Mediators Inflamm. 2017;2017:9870679
pubmed: 28694566
PLoS One. 2015 Jul 21;10(7):e0133476
pubmed: 26197240
Bioinformation. 2019 Apr 15;15(4):277-286
pubmed: 31285645
Clin Microbiol Rev. 2014 Jan;27(1):68-88
pubmed: 24396137
Eukaryot Cell. 2011 Jun;10(6):803-19
pubmed: 21531874
Indian J Crit Care Med. 2015 Mar;19(3):151-4
pubmed: 25810610
Cell Mol Life Sci. 2002 Jun;59(6):903-8
pubmed: 12169020
J Fungi (Basel). 2017 Mar 01;3(1):
pubmed: 29371530
FEMS Yeast Res. 2011 Dec;11(8):621-30
pubmed: 22093746
Clin Infect Dis. 2015 Dec 1;61 Suppl 6:S612-7
pubmed: 26567278
Eukaryot Cell. 2003 Dec;2(6):1200-10
pubmed: 14665455
Infection. 2017 Dec;45(6):737-779
pubmed: 28702763
Mol Microbiol. 2006 Mar;59(5):1429-51
pubmed: 16468987
Mol Microbiol. 2008 Mar;67(6):1274-91
pubmed: 18298443
Nat Rev Dis Primers. 2018 May 11;4:18026
pubmed: 29749387
Eukaryot Cell. 2008 Apr;7(4):584-601
pubmed: 18263765
Cold Spring Harb Perspect Med. 2014 May 01;4(5):
pubmed: 24789878
Eukaryot Cell. 2004 Oct;3(5):1147-53
pubmed: 15470242
Antimicrob Agents Chemother. 2013 Jan;57(1):146-54
pubmed: 23089748
J Antimicrob Chemother. 2018 Jan 1;73(suppl_1):i4-i13
pubmed: 29304207
J Biol Chem. 2008 May 16;283(20):13923-33
pubmed: 18362157
Eukaryot Cell. 2008 Nov;7(11):1951-64
pubmed: 18806209
J Antimicrob Chemother. 2022 Feb 23;77(3):585-597
pubmed: 34893830
J Biochem. 2001 Oct;130(4):503-13
pubmed: 11574070
J Biol Chem. 2003 May 30;278(22):20345-57
pubmed: 12644457
J Antimicrob Chemother. 2010 Apr;65(4):761-8
pubmed: 20106864
Yeast. 2019 Dec;36(12):723-731
pubmed: 31423617
Antonie Van Leeuwenhoek. 2008 Aug;94(2):335-42
pubmed: 18278564
mBio. 2015 Jul 28;6(4):e00986
pubmed: 26220968
Bioinformatics. 2011 May 15;27(10):1390-6
pubmed: 21414992
Eukaryot Cell. 2008 May;7(5):814-25
pubmed: 18375620
Trends Cell Biol. 2000 Aug;10(8):322-8
pubmed: 10884684
PLoS Pathog. 2012;8(5):e1002718
pubmed: 22615574
Int J Antimicrob Agents. 2017 Nov;50(5):599-606
pubmed: 28669835
Clin Infect Dis. 2016 Feb 15;62(4):e1-50
pubmed: 26679628
PLoS Pathog. 2013;9(9):e1003625
pubmed: 24039585
Antimicrob Agents Chemother. 2002 May;46(5):1240-5
pubmed: 11959551
Antimicrob Agents Chemother. 2005 Jun;49(6):2226-36
pubmed: 15917516
Future Microbiol. 2013 Oct;8(10):1325-37
pubmed: 24059922
Cell Commun Signal. 2020 Jan 3;18(1):1
pubmed: 31900175
Antimicrob Agents Chemother. 1997 Sep;41(9):1937-9
pubmed: 9303388
PLoS Biol. 2019 Jul 8;17(7):e3000358
pubmed: 31283755
PLoS One. 2012;7(8):e44192
pubmed: 22952924
J Antimicrob Chemother. 2020 May 1;75(5):1187-1193
pubmed: 32011702
Microbiol Mol Biol Rev. 2005 Jun;69(2):262-91
pubmed: 15944456
Appl Microbiol Biotechnol. 2017 Jun;101(12):5033-5043
pubmed: 28424845
PLoS One. 2013;8(3):e57672
pubmed: 23472097
PLoS Pathog. 2020 Jan 16;16(1):e1008201
pubmed: 31945142
FEMS Yeast Res. 2015 Jun;15(4):fov016
pubmed: 25878052
Methods Enzymol. 2003;366:289-304
pubmed: 14674256
Front Microbiol. 2016 Dec 15;7:1995
pubmed: 28018323
PLoS Pathog. 2010 Aug 26;6(8):e1001069
pubmed: 20865172
FEMS Microbiol Lett. 2009 Apr;293(2):160-9
pubmed: 19260966
Eukaryot Cell. 2014 Jun;13(6):694-705
pubmed: 24681686
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014 Jun;158(2):212-20
pubmed: 23640031
Antimicrob Agents Chemother. 2003 Mar;47(3):956-64
pubmed: 12604527
Infect Dis Clin North Am. 2016 Mar;30(1):1-11
pubmed: 26739604
Elife. 2013 Jan 29;2:e00471
pubmed: 23386978
Antimicrob Agents Chemother. 2010 Apr;54(4):1639-43
pubmed: 20100876
J Fungi (Basel). 2017 Oct 18;3(4):
pubmed: 29371573
Fungal Genet Biol. 2017 Oct;107:44-50
pubmed: 28822858