Abstract
SummaryThe recalcitrance of many bacterial infections to antibiotic treatment is thought to be due to the presence of persisters that are non-growing, antibiotic-insensitive cells. Eventually, persisters resume growth, accounting for relapses of infection. Salmonella is an important pathogen that causes disease through its ability to survive inside macrophages. After macrophage phagocytosis, a significant proportion of the Salmonella population forms non-growing persisters through the action of toxin-antitoxin modules. Here we reveal that one such toxin, TacT, is an acetyltransferase that blocks the primary amine group of amino acids on charged tRNA molecules, thereby inhibiting translation and promoting persister formation. Furthermore, we report the crystal structure of TacT and note unique structural features, including two positively charged surface patches that are essential for toxicity. Finally, we identify a detoxifying mechanism in Salmonella wherein peptidyl-tRNA hydrolase counteracts TacT-dependent growth arrest, explaining how bacterial persisters can resume growth.
Highlights
Chronic and relapsing infections are a major problem to human health as such infections can cause considerable morbidity and frequently require multiple courses of antibiotics, which in turn are thought to contribute to the emergence of stable antibiotic resistance
By investigating the activity and target of one of these Gcn5 N-acetyltransferases (GNATs) toxins, T8, we reveal that this toxin governs Salmonella entry into the persister state through acetylation of aminoacyl-tRNA molecules, thereby halting translation
We modeled the coupled acceptor stem of the phosphodiester backbone lying in the groove with phosphate groups interacting with the sidechains of Arg-91, Lys-33, and Lys-36 (Figure 4A) and the positive surface of the a2 region positioned to interact with phosphates from the remainder of the tRNA molecule, with sidechains of Arg-77, Arg-78, Lys-146, and Arg-158 involved
Summary
Chronic and relapsing infections are a major problem to human health as such infections can cause considerable morbidity and frequently require multiple courses of antibiotics, which in turn are thought to contribute to the emergence of stable antibiotic resistance. Such long-lasting infections are caused by a variety of bacteria, including Mycobacterium tuberculosis, Salmonella, Pseudomonas, pathogenic Escherichia coli, Staphylococcus, and Streptococcus species. The recalcitrance of these infections to antibiotic treatment is thought to be due, at least in part, to the presence of persister cells (Helaine and Kugelberg, 2014; Mulcahy et al, 2010) that are multi-drug tolerant. Typhimurium causes disease by proliferating inside mammalian cells, including macrophages
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