An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance.
DnaJ
DnaK
Hsp70
antibiotic adjuvants
chaperones
cofactors
mycobacteria
proteostasis
resistance
tuberculosis
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
19 05 2022
19 05 2022
Historique:
received:
05
06
2021
revised:
20
09
2021
accepted:
02
11
2021
pubmed:
25
11
2021
medline:
25
5
2022
entrez:
24
11
2021
Statut:
ppublish
Résumé
DnaK is the bacterial homolog of Hsp70, an ATP-dependent chaperone that helps cofactor proteins to catalyze nascent protein folding and salvage misfolded proteins. In the pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), DnaK and its cofactors are proposed antimycobacterial targets, yet few small-molecule inhibitors or probes exist for these families of proteins. Here, we describe the repurposing of a drug called telaprevir that is able to allosterically inhibit the ATPase activity of DnaK and to prevent chaperone function by mimicking peptide substrates. In mycobacterial cells, telaprevir disrupts DnaK- and cofactor-mediated cellular proteostasis, resulting in enhanced efficacy of aminoglycoside antibiotics and reduced resistance to the frontline TB drug rifampin. Hence, this work contributes to a small but growing collection of protein chaperone inhibitors, and it demonstrates that these molecules disrupt bacterial mechanisms of survival in the presence of different antibiotic classes.
Identifiants
pubmed: 34818532
pii: S2451-9456(21)00481-5
doi: 10.1016/j.chembiol.2021.11.004
pmc: PMC9124243
mid: NIHMS1761030
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
Bacterial Proteins
0
Escherichia coli Proteins
0
HSP70 Heat-Shock Proteins
0
Molecular Chaperones
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
854-869.e9Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIH HHS
ID : S10 OD010582
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
EMBO J. 1997 Apr 1;16(7):1501-7
pubmed: 9130695
Cell Stress Chaperones. 2009 Jan;14(1):1-21
pubmed: 18686016
FEBS Lett. 2003 Jan 2;533(1-3):119-23
pubmed: 12505170
J Med Chem. 2003 Sep 25;46(20):4265-72
pubmed: 13678405
J Med Chem. 2016 Jun 23;59(12):5563-86
pubmed: 26844689
J Bacteriol. 2017 Mar 14;199(7):
pubmed: 28096448
Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):E7947-E7956
pubmed: 27872278
ACS Chem Biol. 2013 Sep 20;8(9):1988-1997
pubmed: 23819499
J Med Chem. 2010 Jul 22;53(14):5240-7
pubmed: 20565063
Biochemistry. 2010 Feb 16;49(6):1338-45
pubmed: 20078127
Mol Microbiol. 2003 Apr;48(1):77-84
pubmed: 12657046
Nat Struct Biol. 2000 Jul;7(7):586-93
pubmed: 10876246
PLoS Genet. 2014 Jul 24;10(7):e1004516
pubmed: 25058675
FEBS Lett. 2004 May 7;565(1-3):65-9
pubmed: 15135054
Science. 1996 Jun 14;272(5268):1606-14
pubmed: 8658133
PLoS One. 2014 Jul 24;9(7):e103518
pubmed: 25058147
PLoS Pathog. 2019 Sep 19;15(9):e1007975
pubmed: 31536613
Biochemistry. 2020 May 26;59(20):1946-1960
pubmed: 32326704
ACS Med Chem Lett. 2013 Nov 14;4(11):
pubmed: 24312699
Cell Mol Life Sci. 2011 Jul;68(13):2317-30
pubmed: 21594684
Nat Protoc. 2015 Jun;10(6):845-58
pubmed: 25950237
J Biol Chem. 2015 Apr 3;290(14):8849-62
pubmed: 25635056
J Biol Chem. 1995 Jul 14;270(28):16903-10
pubmed: 7622507
Proc Natl Acad Sci U S A. 2009 May 26;106(21):8471-6
pubmed: 19439666
Front Chem. 2020 Dec 01;8:607769
pubmed: 33335890
J Med Chem. 1994 Oct 14;37(21):3614-21
pubmed: 7932588
Res Microbiol. 1991 May;142(4):437-43
pubmed: 1871430
J Med Chem. 2014 Feb 27;57(4):1188-207
pubmed: 24548207
J Biol Chem. 2010 Jul 9;285(28):21282-91
pubmed: 20439464
Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2865-73
pubmed: 26038563
J Biol Chem. 1995 Dec 15;270(50):30051-9
pubmed: 8530409
Nat Commun. 2020 Jun 19;11(1):3105
pubmed: 32561723
Biochemistry. 2005 Sep 20;44(37):12307-15
pubmed: 16156644
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Nov;1862(11):1340-1354
pubmed: 28110100
Chem Biol. 2005 Jun;12(6):621-37
pubmed: 15975507
Curr Protoc Chem Biol. 2009 Dec 1;1(1):1-15
pubmed: 23839960
Cell Rep. 2012 Mar 29;1(3):251-64
pubmed: 22832197
Protein Pept Lett. 2009;16(6):571-81
pubmed: 19519514
Chem Biol Drug Des. 2013 Jan;81(1):136-47
pubmed: 23253135
J Biol Chem. 2014 Jan 17;289(3):1402-14
pubmed: 24318877
J Med Chem. 2021 Jun 10;64(11):7060-7082
pubmed: 34009983
Mol Cell. 2006 Feb 3;21(3):359-67
pubmed: 16455491
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18297-302
pubmed: 25489079
J Mol Biol. 1994 Jan 21;235(3):848-54
pubmed: 8289323
Sci Rep. 2020 Aug 14;10(1):13831
pubmed: 32796891
J Biol Chem. 2012 Dec 7;287(50):41939-54
pubmed: 23091061
Mol Pharmacol. 1994 May;45(5):978-82
pubmed: 8190112
PLoS One. 2015 Apr 23;10(4):e0124563
pubmed: 25905464
Chem Biol. 2013 Dec 19;20(12):1469-80
pubmed: 24239008
J Mol Biol. 2013 Jul 24;425(14):2463-79
pubmed: 23562829
Top Curr Chem. 2013;328:99-153
pubmed: 22576356
EMBO J. 2010 Apr 21;29(8):1412-22
pubmed: 20300061
Annu Rev Biochem. 2013;82:323-55
pubmed: 23746257
Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):7814-7823
pubmed: 32198203
Curr Top Microbiol Immunol. 2019;420:49-72
pubmed: 30178262
J Biol Chem. 2018 Jul 6;293(27):10796-10809
pubmed: 29764935
Antimicrob Agents Chemother. 1988 Nov;32(11):1680-3
pubmed: 3075437
J Biol Chem. 2015 Apr 17;290(16):10083-92
pubmed: 25739641
Nat Protoc. 2011 Mar;6(3):365-87
pubmed: 21372817
EMBO J. 1989 May;8(5):1461-7
pubmed: 2670554
FEBS Lett. 2007 Jul 31;581(19):3702-10
pubmed: 17544402
PLoS One. 2013 Nov 12;8(11):e78443
pubmed: 24265689
Science. 2005 Sep 30;309(5744):2185-9
pubmed: 16195452
Proc Natl Acad Sci U S A. 2011 May 17;108(20):8206-11
pubmed: 21525416
Science. 2016 Jul 1;353(6294):aac4354
pubmed: 27365453
J Biol Chem. 1995 Nov 3;270(44):26677-82
pubmed: 7592894
J Biol Chem. 2006 Jan 20;281(3):1605-11
pubmed: 16275641
Biotechniques. 2010 Jun;48(6):463-5
pubmed: 20569222
J Biol Chem. 2008 Oct 3;283(40):27100-9
pubmed: 18684711
PLoS Biol. 2013 Oct;11(10):e1001692
pubmed: 24204207
J Bacteriol. 1990 Sep;172(9):4827-35
pubmed: 2144273
Mol Cell. 2012 Dec 28;48(6):863-74
pubmed: 23123194
J Med Chem. 2018 Jul 26;61(14):6163-6177
pubmed: 29953808
Trends Microbiol. 2016 Nov;24(11):862-871
pubmed: 27430191
Cell. 2021 Aug 19;184(17):4579-4592.e24
pubmed: 34297925
PLoS Pathog. 2011 Sep;7(9):e1002251
pubmed: 21980284
ACS Med Chem Lett. 2020 Mar 12;11(3):232-236
pubmed: 32184949
Mol Microbiol. 2021 Feb;115(2):272-289
pubmed: 32996193
Cell. 1990 Sep 7;62(5):939-44
pubmed: 2203539
Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):11970-11975
pubmed: 30397123
J Med Chem. 2010 Oct 28;53(20):7280-6
pubmed: 20608738
Genome Biol Evol. 2016 Oct 5;8(9):2979-2991
pubmed: 27497316
Curr Chem Genomics. 2008 Dec 30;2:90-5
pubmed: 20161846
Protein Pept Lett. 2009;16(6):606-12
pubmed: 19519518
Nat Struct Biol. 1997 May;4(5):342-9
pubmed: 9145101
Front Mol Biosci. 2015 Oct 09;2:57
pubmed: 26501065
Chembiochem. 2008 Dec 15;9(18):2958-61
pubmed: 19031436
Anal Biochem. 2008 Jan 15;372(2):167-76
pubmed: 17904512
Chem Biol. 2011 Feb 25;18(2):210-21
pubmed: 21338918
J Bacteriol. 2001 Oct;183(19):5482-90
pubmed: 11544208
Eur J Biochem. 2002 Sep;269(17):4226-37
pubmed: 12199701
J Med Chem. 2010 Jun 24;53(12):4585-602
pubmed: 20334364
Proteomics. 2016 Apr;16(8):1225-37
pubmed: 26648572
Gene. 1999 Apr 29;231(1-2):95-104
pubmed: 10231573
ACS Infect Dis. 2018 Apr 13;4(4):478-498
pubmed: 29465983
mBio. 2021 Mar 30;12(2):
pubmed: 33785614
Nat Chem. 2012 Jan 24;4(2):90-8
pubmed: 22270643
J Gen Microbiol. 1992 Mar;138(3):551-61
pubmed: 1375623
ACS Infect Dis. 2019 Jun 14;5(6):816-828
pubmed: 30969100
Nat Rev Mol Cell Biol. 2010 Jul;11(7):515-28
pubmed: 20531426
J Biol Chem. 2019 Feb 8;294(6):2151-2161
pubmed: 30213856
ACS Infect Dis. 2020 Oct 9;6(10):2629-2640
pubmed: 32810395
Elife. 2017 Oct 24;6:
pubmed: 29064368
FEBS Lett. 2020 Sep;594(17):2770-2781
pubmed: 32446288
Biochemistry. 2001 Mar 13;40(10):3016-26
pubmed: 11258915
Chem Sci. 2020 Jan 10;11(7):1892-1904
pubmed: 34123282
J Med Chem. 2014 Feb 27;57(4):1208-24
pubmed: 24548239