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One promising strategy is to develop resistance\u2010breaker compounds, which inhibit resistance mechanisms and thus resensitize bacteria to existing antibiotics. In the current study, we identify bacterial DNA double\u2010strand break repair as a promising target for the development of resistance\u2010breaking co\u2010therapies. We examined genetic variants of <jats:italic>Escherichia coli<\/jats:italic> that combined antibiotic\u2010resistance determinants with DNA repair defects. We observed that defects in the double\u2010strand break repair pathway led to significant resensitization toward\u00a0five bactericidal antibiotics representing different functional classes. Effects ranged from partial to full resensitization. For ciprofloxacin and nitrofurantoin, sensitization manifested as a reduction in the minimum inhibitory concentration. For kanamycin and trimethoprim, sensitivity manifested through increased rates of killing at high antibiotic concentrations. For ampicillin, repair defects dramatically reduced antibiotic tolerance. Ciprofloxacin, nitrofurantoin, and trimethoprim induce the promutagenic SOS response. Disruption of double\u2010strand break repair strongly dampened the induction of SOS by these antibiotics. Our findings suggest that if break\u2010repair inhibitors can be developed they could resensitize antibiotic\u2010resistant bacteria to multiple classes of existing antibiotics and may suppress the development of de novo antibiotic\u2010resistance mutations.<\/jats:p>","DOI":"10.1002\/mbo3.1316","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T08:25:52Z","timestamp":1663921552000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Defects in DNA double\u2010strand break repair resensitize antibiotic\u2010resistant <i>Escherichia coli<\/i>\u00a0to multiple bactericidal antibiotics"],"prefix":"10.1002","volume":"11","author":[{"given":"Sarah A.","family":"Revitt\u2010Mills","sequence":"first","affiliation":[{"name":"School of Chemistry and Molecular Bioscience, Molecular Horizons Institute University of Wollongong  Wollongong New South Wales Australia"},{"name":"Illawarra Health 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