Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance

TLDR

Drug‑resistant bacteria pose a serious threat to human health, with quinolone and rifamycin antibiotics rapidly selecting for chromosomal mutations during therapy. The study aims to prevent SOS‑mediated mutation by inhibiting LexA protease, thereby blocking E. coli evolution of resistance to ciprofloxacin and rifampicin. The authors inhibit LexA protease to block SOS induction, preventing derepression of error‑prone polymerases during DNA repair.

Abstract

The emergence of drug-resistant bacteria poses a serious threat to human health. In the case of several antibiotics, including those of the quinolone and rifamycin classes, bacteria rapidly acquire resistance through mutation of chromosomal genes during therapy. In this work, we show that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic Escherichia coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, important quinolone and rifamycin antibiotics. We show in vitro that LexA cleavage is induced during RecBC-mediated repair of ciprofloxacin-mediated DNA damage and that this results in the derepression of the SOS-regulated polymerases Pol II, Pol IV and Pol V, which collaborate to induce resistance-conferring mutations. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.