Transcriptional regulation of the Type I TA system timPR by two efflux pump repressors

Toxin-antitoxin (TA) systems are genetic modules commonly found in bacterial genomes that consist of a toxin gene and its cognate antitoxin. These systems have been suggested to play a role in a range of stress responses, plasmid maintenance, anti-phage defense and bacterial persistence. So far 8 different types of TA systems exist and the classification is based on the nature and mechanism of action of the antitoxin. In general, toxins are stable proteins that inhibit essential cellular functions, while antitoxins can be proteins or RNAs that neutralize the toxins under regular laboratory growth conditions. In Type I TA systems, the systems we are focusing on, the toxin is a small hydrophobic protein that inserts into the inner membrane and disrupts its integrity while the antitoxin is an antisense RNA that inhibits toxin expression post-transcriptionally.

The concept that bacterial toxin-antitoxin (TA) systems contribute to antibiotic persistence especially via toxin-induced dormancy has generated significant interest. Initial studies identified HipA (from the hipAB TA system) as a key toxin increasing persistence, supporting the idea that toxins can induce a drug-tolerant persister state. Type I toxins, such as TisB and HokB, form pores in the membrane, disrupting the proton motive force (PMF) and depleting ATP, which slows cellular activity and promotes persistence. Moreover, recent findings suggest that type I toxins may also impede antibiotic uptake by interfering with membrane transport systems, further enhancing survival under antibiotic stress. However, for most of these systems the above implications in antibiotic persistence are seen through overexpression of the toxins. Despite advances, the environmental cues that trigger toxin expression remain unclear.