Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics.
Anti-Bacterial Agents
/ biosynthesis
Bacteria
/ genetics
Bacterial Proteins
/ genetics
Biocatalysis
Biosynthetic Pathways
Chromatography, High Pressure Liquid
Drug Resistance, Microbial
/ genetics
Humans
Isoquinolines
/ chemistry
Mass Spectrometry
/ methods
Molecular Dynamics Simulation
Molecular Structure
NADP
/ chemistry
Naphthyridines
/ chemistry
Oxidation-Reduction
Oxidoreductases
/ genetics
Tetrahydroisoquinolines
/ chemistry
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 12 2021
06 12 2021
Historique:
received:
20
04
2021
accepted:
11
11
2021
entrez:
7
12
2021
pubmed:
8
12
2021
medline:
11
1
2022
Statut:
epublish
Résumé
Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore. Correspondingly, antibiotic producer has canonically co-evolved this approach with the biosynthetic capability for self-resistance. Here we discover a self-defense strategy featuring with reductive inactivation of hemiaminal pharmacophore by short-chain dehydrogenases/reductases (SDRs) NapW and homW, which are integrated with the naphthyridinomycin biosynthetic pathway. We determine the crystal structure of NapW·NADPH complex and propose a catalytic mechanism by molecular dynamics simulation analysis. Additionally, a similar detoxification strategy is identified in the biosynthesis of saframycin A, another member of tetrahydroisoquinoline (THIQ) antibiotics. Remarkably, similar SDRs are widely spread in bacteria and able to inactive other THIQ members including the clinical anticancer drug, ET-743. These findings not only fill in the missing intracellular events of temporal-spatial shielding mode for cryptic self-resistance during THIQs biosynthesis, but also exhibit a sophisticated damage-control in secondary metabolism and general immunity toward this family of antibiotics.
Identifiants
pubmed: 34873166
doi: 10.1038/s41467-021-27404-3
pii: 10.1038/s41467-021-27404-3
pmc: PMC8648761
doi:
Substances chimiques
Anti-Bacterial Agents
0
Bacterial Proteins
0
Isoquinolines
0
Naphthyridines
0
Tetrahydroisoquinolines
0
NADP
53-59-8
naphthyridinomycin
62046-87-1
Oxidoreductases
EC 1.-
saframycin A
MJW34HDB0D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7085Informations de copyright
© 2021. The Author(s).
Références
Bioresour Technol. 2010 Sep;101(17):6761-7
pubmed: 20382525
J Comput Chem. 2009 Dec;30(16):2785-91
pubmed: 19399780
Nat Chem Biol. 2015 Sep;11(9):671-7
pubmed: 26284674
J Mol Biol. 2019 Aug 23;431(18):3370-3399
pubmed: 31288031
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Acta Crystallogr D Biol Crystallogr. 2006 Aug;62(Pt 8):859-66
pubmed: 16855301
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
Nat Prod Rep. 2020 Jul 1;37(7):879-892
pubmed: 31912842
Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):11232-11237
pubmed: 30327344
Nat Rev Microbiol. 2017 Jul;15(7):422-434
pubmed: 28392565
Angew Chem Int Ed Engl. 2014 May 5;53(19):4840-4
pubmed: 24706593
Science. 2019 Jan 18;363(6424):270-275
pubmed: 30573544
Chem Biol. 2015 Mar 19;22(3):336-41
pubmed: 25772467
Angew Chem Int Ed Engl. 2021 Apr 12;60(16):8990-8996
pubmed: 33538390
Antimicrob Agents Chemother. 1998 Nov;42(11):2985-8
pubmed: 9797237
Curr Opin Biotechnol. 2021 Jun;69:128-135
pubmed: 33450704
Angew Chem Int Ed Engl. 2021 Mar 15;60(12):6639-6645
pubmed: 33314510
Commun Biol. 2019 Dec 6;2:454
pubmed: 31840099
Cell Chem Biol. 2019 Apr 18;26(4):559-570.e6
pubmed: 30799223
J Am Chem Soc. 2018 Dec 5;140(48):16641-16649
pubmed: 30422653
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W375-83
pubmed: 17452350
Cell Mol Life Sci. 2008 Dec;65(24):3895-906
pubmed: 19011750
Nat Rev Microbiol. 2015 Jan;13(1):42-51
pubmed: 25435309
J Biol Chem. 2012 Feb 10;287(7):5112-21
pubmed: 22187429
Nat Commun. 2017 Nov 14;8(1):1485
pubmed: 29133784
mBio. 2020 Feb 4;11(1):
pubmed: 32019788
J Bacteriol. 2008 Jan;190(1):251-63
pubmed: 17981978
Nature. 2020 Feb;578(7796):582-587
pubmed: 32051588
Chem Biol Interact. 2003 Feb 1;143-144:247-53
pubmed: 12604210
J Am Chem Soc. 2019 Dec 11;141(49):19208-19213
pubmed: 31743008
Cell Chem Biol. 2018 Sep 20;25(9):1075-1085.e4
pubmed: 29937405
Curr Top Med Chem. 2016;16(15):1717-26
pubmed: 26456466
J Am Chem Soc. 2017 Dec 13;139(49):17719-17722
pubmed: 29112397
Nat Prod Rep. 2015 Feb;32(2):328-47
pubmed: 25273374
Nat Chem Biol. 2010 Jun;6(6):408-10
pubmed: 20453862
Proc Natl Acad Sci U S A. 2012 May 29;109(22):8540-5
pubmed: 22586110
Nat Chem Biol. 2018 Jun;14(6):556-564
pubmed: 29713061
Chem Rev. 2002 May;102(5):1669-730
pubmed: 11996547
Chem Rev. 2005 Feb;105(2):395-424
pubmed: 15700950
Org Lett. 2013 Jul 19;15(14):3674-7
pubmed: 23841701
Chem Sci. 2019 Nov 18;11(2):364-371
pubmed: 32190259
Angew Chem Int Ed Engl. 2017 Jul 24;56(31):9116-9120
pubmed: 28561936
Chem Rev. 2006 Feb;106(2):233-52
pubmed: 16464004
Nat Chem Biol. 2018 Apr;14(4):381-387
pubmed: 29483640
Angew Chem Int Ed Engl. 2019 Mar 18;58(12):3972-3975
pubmed: 30689274
Curr Opin Chem Biol. 2018 Dec;47:101-108
pubmed: 30268903
Biochem Pharmacol. 2000 Aug 15;60(4):457-70
pubmed: 10874120
ACS Chem Biol. 2018 Jun 15;13(6):1426-1437
pubmed: 29763292
Nat Commun. 2018 Aug 6;9(1):3095
pubmed: 30082794