Toxin–antitoxin systems are widespread genetic modules in bacteria that play key roles in stress responses, persistence, and survival by regulating growth and stabilising mobile genetic elements. The sole VapBC type II toxin‑antitoxin system in Neisseria gonorrhoeae, referred to as FitAB, has previously been implicated in intracellular replication and transcytosis1, yet the mechanistic details remain unresolved.
Here we combine analyses of infection dynamics with an assessment of natural transformation, alongside transcriptomic profiling and DNA sequencing to define the cellular processes disrupted by fitAB inactivation. The loss of FitAB enhances host cell association (adherence) and intracellular survival. Beyond this, we demonstrate that FitAB also influences natural transformation, an additional core virulence-associated process involved in gonococcal pathogenesis. Transcriptomic profiling revealed extensive transcriptional rewiring dominated by pil-associated loci during in vitro growth, suggestive of altered antigenic variation of the gonococcal type IV pilus. We therefore propose that FitAB promotes adherence and intracellular residence indirectly by modulating homologous recombination processes, including antigenic variation of the type IV pilus, which is known to facilitate intracellular traversal. Although the precise molecular mechanism remains to be defined, these findings establish FitAB as a core regulator of gonococcal infection acting through central virulence-associated pathways.