Shared mechanisms of enhanced plasmid maintenance and antibiotic tolerance mediated by the VapBC toxin:antitoxin system

Journal article

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, VapB^L12C mediates high-level plasmid stabilization because VapB^L12 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 VapB^L12. Our findings highlight the links between plasmid maintenance and antibiotic tolerance, both of which can promote the development of antimicrobial resistance.

Authors: Hollingshead, S; McVicker, G; Nielsen, MR; Zhang, Y; Pilla, G

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Microbiology
• Journal: mBio
• Volume: 16
• Issue: 2
• Article number: e02616-24
• Publication date: 2024-12-20
• Acceptance date: 2024-11-12
• DOI: 10.1128/mbio.02616-24
• EISSN: 2150-7511
• ISSN: 2161-2129
• Pmid: 39704502
• Language: English
• Keywords: antibiotic tolerance; TA systems; plasmid stability; VapBC; Shigella