Dual Toxic-Peptide-Coding Staphylococcus aureus RNA under Antisense Regulation Targets Host Cells and Bacterial Rivals Unequally

Summary: Produced from the pathogenicity islands of Staphylococcus aureus clinical isolates, stable SprG1 RNA encodes two peptides from a single internal reading frame. These two peptides accumulate at the membrane, and inducing their expression triggers S. aureus death. Replacement of the two initiation codons by termination signals reverses this toxicity. During growth, cis-antisense RNA SprF1 is expressed, preventing mortality by reducing SprG1 RNA and peptide levels. The peptides are secreted extracellularly, where they lyse human host erythrocytes, a process performed more efficiently by the longer peptide. The two peptides also inactivate Gram-negative and -positive bacteria, with the shorter peptide more effective against S. aureus rivals. Two peptides are secreted from an individual RNA containing two functional initiation codons. Thus, we present an unconventional type I toxin-antitoxin system expressed from a human pathogen producing two hemolytic and antibacterial peptides from a dual-coding RNA, negatively regulated by a dual-acting antisense RNA. : Pinel-Marie et al. present an unconventional type I toxin-antitoxin system expressed by Staphylococcus aureus. A dual-coding RNA produces two membrane and secreted toxic peptides by utilizing two initiation codons. Their expression is prevented by a dual-acting RNA antitoxin. The membrane peptides investigate programmed cell death inducing the release of virulence factors. The secreted peptides lyse host cells and competing bacteria to facilitate infections. Multiple initiation codons contribute to diversity through expression of peptide isoforms. In pathogens, programmed toxin expression could point to new antibacterials