A Salmonella type I toxin promotes systemic infection by inhibiting F _o F ₁ ATP synthase

Intracellular pathogens including Salmonella Typhimurium survive within macrophage phagosomes by forming non-replicating persisters. Toxins from toxin-antitoxin systems have been implicated in persister formation as key contributors, although the biological targets of toxins remain largely unknown. Here, we report that Salmonella IbsA, a 19-amino-acid-long type I toxin, induces growth arrest and decreases intracellular ATP levels. An unbiased large-scale bacterial two-hybrid screen identified 54 IbsA-interacting targets, including proteins involved in oxidative phosphorylation and cell division. Among these, IbsA toxin specifically targets two subunits of the bacterial F _o F ₁ ATP synthase. IbsA interacts with the a and b subunits in the membrane-bound F _o sector and inhibits proton translocation, thereby decreasing ATP levels. In turn, this IbsA-mediated decrease facilitates Salmonella spread between macrophages, promoting systemic infection. Accordingly, ibsA deletion decreases bacterial burden in organs and attenuates mouse virulence. Therefore, unlike other bacterial toxins, the IbsA toxin enhances Salmonella pathogenicity by decreasing the bacterium’s ATP levels.