Mechanistic insights into plasmid transfer inhibition in Enterobacterales by nucleoside analogues

This study explores a novel strategy to combat antimicrobial resistance (AMR) by inhibiting plasmid conjugation—the key mechanism by which resistance genes spread between bacteria. Researchers tested clinically approved nucleoside analogues and found that several (including azidothymidine, didanosine, stavudine, and trifluridine) significantly reduced the transfer of resistance-carrying plasmids in Escherichia coli and Klebsiella pneumoniae without affecting bacterial growth. However, some compounds unexpectedly increased plasmid transfer, highlighting complex underlying biology. Mechanistic analyses revealed that factors such as bacterial motility, DNA damage response, and metabolic pathways (e.g., methionine metabolism) play important roles in conjugation. Overall, the findings suggest that existing drugs could be repurposed as inhibitors of resistance gene spread, offering a promising complementary approach to tackling AMR.