Journal Article

PUBDB-2025-01441

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Shared mechanisms of enhanced plasmid maintenance and antibiotic tolerance mediated by the VapBC toxin:antitoxin system

Hollingshead, S. ; McVicker, G. ; Nielsen, M. R. ; Zhang, Y. ; Pilla, G. ; Jones, R. A. ; Thomas, J. C. ; Johansen, S. E. H. ; Exley, R. M. ; Brodersen, D. E. (Corresponding author)Extern*EMBL* ; Tang, C. M. (Corresponding author)

2025
American Society for Microbiology Washington, DC

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Please use a persistent id in citations: doi:10.1128/mbio.02616-24  doi:10.3204/PUBDB-2025-01441

Abstract: Toxin:antitoxin (TA) systems are widespread in bacteria and were first identified as plasmid addiction systems that kill bacteria lacking a TA-encoding plasmid following cell division. TA systems have also been implicated in bacterial persistence and antibiotic tolerance, which can be precursors of antibiotic resistance. Here, we identified a clinical isolate of Shigella sonnei (CS14) with a remarkably stable pINV virulence plasmid; pINV is usually frequently lost from S. sonnei, but plasmid loss was not detected from CS14. We found that the plasmid in CS14 is stabilized by a single nucleotide polymorphism (SNP) in its vapBC TA system. VapBC TA systems are the most common Type II TA system in bacteria, and consist of a VapB antitoxin and VapC PIN domain-containing toxin. The plasmid stabilizing SNP leads to a Q12L substitution in the DNA-binding domain of VapB, which reduces VapBC binding to its own promoter, impairing vapBC autorepression. However, VapBL12C mediates high-level plasmid stabilization because VapBL12 is more prone to degradation by Lon than wild-type VapB; this liberates VapC to efficiently kill bacteria that no longer contain a plasmid. Of note, mutations that confer tolerance to antibiotics in Escherichia coli also map to the DNA-binding domain of VapBC encoded by the chromosomally integrated F plasmid. We demonstrate that the tolerance mutations also enhance plasmid stabilization by the same mechanism as VapBL12. Our findings highlight the links between plasmid maintenance and antibiotic tolerance, both of which can promote the development of antimicrobial resistance.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2025

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