Evolution of antibiotic resistance is a world health crisis, fueled by new mutations

Zhai, Y.; Pribis, J. P.; Dooling, S. W.; Garcia-Villada, L.; Minnick, P. J.; Xia, J.; Liu, J.; Mei, Q.; Fitzgerald, D. M.; Herman, C.; Hastings, P. J.; (8) Costa-Mattioli, M.; Rosenberg, S. M.
Science Advances 9 (25), eadg0188 (2023)

Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life of antibiotics, yet evolution-slowing drugs and drug targets have been underexplored and ineffective

Here, we used a network-based strategy to identify drugs that block hubs of fluoroquinolone antibiotic-induced mutagenesis. We identify a U.S. Food and Drug Administration– and European Medicines Agency–approved drug, dequalinium chloride (DEQ), that inhibits activation of the Escherichia coli general stress response, which promotes ciprofloxacin-induced (stress-induced) mutagenic DNA break repair. We uncover the step in the pathway inhibited: activation of the upstream “stringent” starvation stress response, and find that DEQ slows evolution without favoring proliferation of DEQ-resistant mutants. Furthermore, we demonstrate stress-induced mutagenesis during mouse infections and its inhibition by DEQ. Our work provides a proof-of-concept strategy for drugs to slow evolution in bacteria and generally.

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