Active destabilization of the integron synaptic complex reduces bacterial adaptation to antibiotics

Abstract

Antibiotic multi-resistance (AMR) in bacteria poses a significant threat to global health, driven by mechanisms like the integron genetic system in Gram-negative bacteria. Integrons facilitate AMR by shuffling resistance genes through site-specific recombination, mediated by the integrase enzyme IntI. Earlier studies revealed that the mechanical stability of the synaptic complex, a structure formed by four integrase subunits and DNA, correlates with the recombination efficiency, and, by extension, the adaptation capability. We identified a conserved C-terminal -helix in IntI that stabilizes the synaptic complex via specific interactions with a binding pocket. To disrupt this interaction, we designed peptides mimicking the -helix, which reduced the mechanical stability probed with single-molecule optical tweezers. In bacterial adaptation assays, these peptides significantly decreased integron-mediated adaptation to ciprofloxacin stress without exhibiting antimicrobial activity. This approach highlights a novel strategy to combat AMR by targeting integron-mediated gene shuffling, offering potential for future therapeutic development to limit the spread of resistance genes.