Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria.
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
04
10
2022
accepted:
07
06
2023
medline:
14
8
2023
pubmed:
10
8
2023
entrez:
10
8
2023
Statut:
epublish
Résumé
Antibiotic resistance is a continuously increasing concern for public healthcare. Understanding resistance mechanisms and their emergence is crucial for the development of new antibiotics and their effective use. The peptide antibiotic albicidin is such a promising candidate that, as a gyrase poison, shows bactericidal activity against a wide range of gram-positive and gram-negative bacteria. Here, we report the discovery of a gene amplification-based mechanism that imparts an up to 1000-fold increase in resistance levels against albicidin. RNA sequencing and proteomics data show that this novel mechanism protects Salmonella Typhimurium and Escherichia coli by increasing the copy number of STM3175 (YgiV), a transcription regulator with a GyrI-like small molecule binding domain that traps albicidin with high affinity. X-ray crystallography and molecular docking reveal a new conserved motif in the binding groove of the GyrI-like domain that can interact with aromatic building blocks of albicidin. Phylogenetic studies suggest that this resistance mechanism is ubiquitous in gram-negative bacteria, and our experiments confirm that STM3175 homologs can confer resistance in pathogens such as Vibrio vulnificus and Pseudomonas aeruginosa.
Identifiants
pubmed: 37561817
doi: 10.1371/journal.pbio.3002186
pii: PBIOLOGY-D-22-02192
pmc: PMC10414762
doi:
Substances chimiques
albicidin
96955-97-4
Anti-Bacterial Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3002186Informations de copyright
Copyright: © 2023 Saathoff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Science. 2012 May 25;336(6084):1030-3
pubmed: 22628654
Proteins. 2002 May 15;47(3):403-7
pubmed: 11948793
J Appl Microbiol. 2006 Jul;101(1):151-60
pubmed: 16834602
J Am Chem Soc. 2015 Jun 24;137(24):7608-11
pubmed: 26057615
Proc Natl Acad Sci U S A. 2021 Jan 5;118(1):
pubmed: 33443214
PLoS Med. 2016 Nov 29;13(11):e1002184
pubmed: 27898664
Antimicrob Agents Chemother. 2007 Jan;51(1):181-7
pubmed: 17074789
Angew Chem Int Ed Engl. 2015 Feb 2;54(6):1969-73
pubmed: 25504839
Protein Sci. 2018 Jan;27(1):293-315
pubmed: 29067766
Chemistry. 2021 Jun 21;27(35):9077-9086
pubmed: 33769627
Nat Ecol Evol. 2020 Apr;4(4):612-625
pubmed: 32152532
J Antibiot (Tokyo). 2019 Nov;72(11):785-792
pubmed: 31451755
Angew Chem Int Ed Engl. 2014 Dec 22;53(52):14605-9
pubmed: 25510965
Annu Rev Genet. 2009;43:167-95
pubmed: 19686082
Nat Protoc. 2015 Jun;10(6):845-58
pubmed: 25950237
J Nat Prod. 2016 Sep 23;79(9):2223-8
pubmed: 27598688
Genetics. 2010 Apr;184(4):1077-94
pubmed: 20083614
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):525-30
pubmed: 11149947
J Biol Chem. 1993 Aug 15;268(23):17495-503
pubmed: 8349629
Chemistry. 2020 Jun 5;26(32):7219-7225
pubmed: 31984562
Science. 2021 Aug 20;373(6557):871-876
pubmed: 34282049
Lancet. 2022 Feb 12;399(10325):629-655
pubmed: 35065702
Appl Environ Microbiol. 1995 Jun;61(6):2302-7
pubmed: 7793951
Proc Biol Sci. 2012 Dec 22;279(1749):5048-57
pubmed: 22977152
Proteins. 2009 Oct;77(1):202-8
pubmed: 19422057
Nat Chem Biol. 2015 Mar;11(3):195-7
pubmed: 25599532
mBio. 2020 Sep 8;11(5):
pubmed: 32900806
Molecules. 2019 Apr 09;24(7):
pubmed: 30970590
Biochemistry. 2016 Aug 30;55(34):4850-63
pubmed: 27505298
Methods Mol Biol. 2020;2112:29-42
pubmed: 32006276
Nature. 2021 Aug;596(7873):583-589
pubmed: 34265844
Nucleic Acids Res. 2022 Jan 7;50(D1):D439-D444
pubmed: 34791371
Nat Microbiol. 2019 Mar;4(3):504-514
pubmed: 30742072
Anim Biotechnol. 2006;17(2):111-24
pubmed: 17127523
J Appl Microbiol. 2010 Jun;108(6):2088-102
pubmed: 19919618
Chem Sci. 2021 Oct 19;12(43):14606-14617
pubmed: 34881013
Cold Spring Harb Perspect Biol. 2015 Feb 02;7(2):a016592
pubmed: 25646380
J Gen Microbiol. 1990 Jan;136(1):51-8
pubmed: 2191080
Mol Microbiol. 2021 Jun;115(6):1122-1137
pubmed: 33247976
Genome Res. 2004 Jun;14(6):1188-90
pubmed: 15173120
Genome Biol Evol. 2014 May 20;6(6):1287-301
pubmed: 24850796
Genetics. 2012 Oct;192(2):397-415
pubmed: 22865732
Nat Struct Biol. 1997 Apr;4(4):269-75
pubmed: 9095194
Mol Microbiol. 1995 Oct;18(2):301-11
pubmed: 8709849
Chemistry. 2019 Dec 20;25(72):16538-16543
pubmed: 31642561
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
Mol Biol Evol. 1998 Aug;15(8):931-42
pubmed: 9718721
J Gen Microbiol. 1985 May;131(5):1069-75
pubmed: 2410547
J Antimicrob Chemother. 2003 Jan;51(1):180-2
pubmed: 12493808
Nat Rev Microbiol. 2009 Aug;7(8):578-88
pubmed: 19609259
Arch Microbiol. 2003 Nov;180(5):339-46
pubmed: 13680098
Nat Struct Biol. 2000 May;7(5):424-30
pubmed: 10802742
Nat Commun. 2018 Aug 6;9(1):3095
pubmed: 30082794