ABCF protein-mediated resistance shapes bacterial responses to antibiotics based on their type and concentration.

ABCF-ATPases are increasingly recognized as translation factors that rescue stalled ribosomes when they encounter difficult mRNA templates or are stalled by antibiotics. The latter defines antibiotic resistance ABCF (ARE ABCF) proteins, known for their role in antibiotic resistance. However, in this study, we reveal a broader role of ARE ABCFs in antibiotic-responsive regulation. Using genetic, OMICs, and biochemical approaches, we showed that ARE ABCF proteins TiaA and Are5sc in IMPORTANCE: Bacteria adapt to diverse stimuli mainly through transcriptional changes that regulate adaptive protein factors. Here, we show that responses to protein synthesis-inhibiting antibiotics are fine-tuned by antibiotic resistance ABCF proteins at the translational level, enabling bacteria to differentiate between antibiotic classes and concentrations for a tailored response. Additionally, we have demonstrated that these proteins can specialize in conferring high-level resistance to specific antibiotics. Given their prevalence in pathogenic bacteria, antibiotic resistance ABCF (ARE ABCF) proteins may play a crucial role in resistance development, particularly against new antibiotics targeting the ribosomal catalytic center, presenting a significant challenge for antimicrobial therapy.