Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 09 2023
09 09 2023
Historique:
received:
05
01
2023
accepted:
25
08
2023
medline:
11
9
2023
pubmed:
10
9
2023
entrez:
9
9
2023
Statut:
epublish
Résumé
There is an arms race between beta-lactam antibiotics development and co-evolving beta-lactamases, which provide resistance by breaking down beta-lactam rings. We have observed that certain beta-lactamases tend to aggregate, which persists throughout their evolution under the selective pressure of antibiotics on their active sites. Interestingly, we find that existing beta-lactamase active site inhibitors can act as molecular chaperones, promoting the proper folding of these resistance factors. Therefore, we have created Pept-Ins, synthetic peptides designed to exploit the structural weaknesses of beta-lactamases by causing them to misfold into intracellular inclusion bodies. This approach restores sensitivity to a wide range of beta-lactam antibiotics in resistant clinical isolates, including those with Extended Spectrum variants that pose significant challenges in medical practice. Our findings suggest that targeted aggregation of resistance factors could offer a strategy for identifying molecules that aid in addressing the global antibiotic resistance crisis.
Identifiants
pubmed: 37689716
doi: 10.1038/s41467-023-41191-z
pii: 10.1038/s41467-023-41191-z
pmc: PMC10492782
doi:
Substances chimiques
Anti-Bacterial Agents
0
Monobactams
0
beta-Lactamase Inhibitors
0
beta-Lactamases
EC 3.5.2.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5571Informations de copyright
© 2023. Springer Nature Limited.
Références
FEMS Microbiol Lett. 2017 Feb 1;364(3):
pubmed: 28087620
Antimicrob Agents Chemother. 2000 Nov;44(11):3003-7
pubmed: 11036013
Bioinformatics. 2014 Oct 15;30(20):2981-2
pubmed: 24996895
Clin Microbiol Rev. 2001 Oct;14(4):933-51, table of contents
pubmed: 11585791
Clin Microbiol Rev. 2005 Oct;18(4):657-86
pubmed: 16223952
J Biol Chem. 1998 Oct 9;273(41):26603-9
pubmed: 9756899
Bioinformatics. 2012 Dec 1;28(23):3150-2
pubmed: 23060610
Lancet Infect Dis. 2010 Sep;10(9):597-602
pubmed: 20705517
Plant Physiol. 2016 Jun;171(2):773-87
pubmed: 27208282
Lancet Infect Dis. 2018 Feb;18(2):132-134
pubmed: 29198739
Science. 2016 Nov 11;354(6313):
pubmed: 27846578
J Enzyme Inhib Med Chem. 2017 Dec;32(1):917-919
pubmed: 28719998
J Dent. 2000 Nov;28(8):565-70
pubmed: 11082524
J Mol Biol. 2015 Jan 30;427(2):236-47
pubmed: 25451783
Protein Eng Des Sel. 2012 Jul;25(7):357-66
pubmed: 22706763
BMC Microbiol. 2017 Apr 27;17(1):101
pubmed: 28449650
J Mol Biol. 2017 Feb 3;429(3):348-355
pubmed: 27914894
J Biol Chem. 2012 Aug 17;287(34):28386-97
pubmed: 22773828
Curr Pharm Biotechnol. 2011 Jun;12(6):916-22
pubmed: 21235448
Nucleic Acids Res. 2008 Jan;36(Database issue):D190-5
pubmed: 18045787
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W382-8
pubmed: 15980494
J Mol Biol. 2010 Dec 17;404(5):832-46
pubmed: 20955714
Clin Microbiol Rev. 2010 Jan;23(1):160-201
pubmed: 20065329
J Mol Biol. 2004 Sep 3;342(1):345-53
pubmed: 15313629
Biochemistry. 2010 Aug 17;49(32):6838-45
pubmed: 20604540
Nat Commun. 2018 Feb 28;9(1):866
pubmed: 29491361
J Vis Exp. 2010 Aug 05;(42):
pubmed: 20729806
Rev Infect Dis. 1988 Jul-Aug;10(4):677-8
pubmed: 3055168
ACS Chem Biol. 2009 Aug 21;4(8):673-84
pubmed: 19624097
Acta Crystallogr D Biol Crystallogr. 1995 Sep 1;51(Pt 5):682-94
pubmed: 15299797
J Mol Biol. 2019 Aug 23;431(18):3472-3500
pubmed: 30959050
Nat Biomed Eng. 2017 Oct;1(10):782-783
pubmed: 31015591
Nature. 2014 May 1;509(7498):S2-3
pubmed: 24784426
Chem Biol. 2009 May 29;16(5):540-7
pubmed: 19477418
Methods Mol Biol. 2018;1676:109-127
pubmed: 28986906
Mol Cell. 2016 Sep 1;63(5):768-80
pubmed: 27570072
Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9629-34
pubmed: 22645360
J Mol Biol. 2006 Feb 3;355(5):1037-47
pubmed: 16359707
FEMS Microbiol Rev. 2010 Nov;34(6):1015-36
pubmed: 20412308
Clin Microbiol Infect. 1996 Feb;2 Suppl 1:S35-S39
pubmed: 11866860
J Antimicrob Chemother. 1983 May;11(5):427-33
pubmed: 6874629
Int J Mol Sci. 2020 Jan 13;21(2):
pubmed: 31940970
Nature. 1965 Oct 16;208(5007):239-41
pubmed: 5326330
Nat Methods. 2010 Mar;7(3):237-42
pubmed: 20154676
Org Biomol Chem. 2011 Dec 21;9(24):8356-70
pubmed: 22051883
Cell. 2012 Mar 16;148(6):1188-203
pubmed: 22424229
Antimicrob Agents Chemother. 2010 Mar;54(3):969-76
pubmed: 19995920
FEBS Lett. 2012 Sep 21;586(19):3330-5
pubmed: 22850115
PLoS One. 2015 Mar 03;10(3):e0118290
pubmed: 25734558
Nat Biotechnol. 2004 Oct;22(10):1302-6
pubmed: 15361882
Antimicrob Agents Chemother. 2009 Dec;53(12):5046-54
pubmed: 19770275
Mol Microbiol. 2016 Mar;99(5):849-65
pubmed: 26559925