The toxin from the PemIK-Sa1 toxin-antitoxin system decreases Staphylococcus aureus resistance to antibiotics

Abstract

Toxin-antitoxin (TA) systems are bacteria-specific components involved in maintaining mobile genetic elements that may carry antibiotic resistance determinants (ARDs), among other functions. PemIK-Sa1 is a plasmid-encoded TA system found in Staphylococcus aureus, a dangerous pathogen affecting humans and animals. The PemK-Sa1 toxin is a sequence-specific ribonuclease inhibited by its cognate antitoxin, PemI-Sa1. Using recombinant multidrug-resistant strains, we demonstrated that expression of the toxin reduces resistance to antibiotics from various classes, including β-lactams, fluoroquinolones, aminoglycosides, and chloramphenicol. Transcriptomics revealed that, in addition to downregulation of genes encoding ARDs, nearly one-third of the staphylococcal transcriptome is altered. Furthermore, proteomic analysis revealed that toxin expression results in the downregulation of several proteins involved in nucleotide biosynthesis, carbohydrate metabolism, and energy production. This indicates parallel mechanisms in which the toxin not only degrades ARD transcripts, thereby directly impacting their function, but also alters the expression of genes encoding proteins crucial to essential cell processes. The ability to reduce resistance to a broad range of antibiotics makes the PemK-Sa1 toxin a promising tool for combating multidrug-resistant bacteria through the artificial activation of the PemIK-Sa1 TA system.