Quinolone Resistance Reversion by Targeting the SOS Response

Abstract

Suppression of the SOS response has been postulated as a therapeutic strategy for potentiating antimicrobial agents. We aimed to evaluate the impact of its suppression on reversing resistance using a model of isogenic strains of Escherichia coli representing multiple levels of quinolone resistance. E. coli mutants exhibiting a spectrum of SOS activity were constructed from isogenic strains carrying quinolone resistance mechanisms with susceptible and resistant phenotypes. Changes in susceptibility were evaluated by static (MICs) and dynamic (killing curves or flow cytometry) methodologies. A peritoneal sepsis murine model was used to evaluate in vivo impact. Suppression of the SOS response was capable of resensitizing mutant strains with genes encoding three or four different resistance mechanisms (up to 15-fold reductions in MICs). Killing curve assays showed a clear disadvantage for survival (Δlog10 CFU per milliliter [CFU/ml] of 8 log units after 24 h), and the in vivo efficacy of ciprofloxacin was significantly enhanced (Δlog10 CFU/g of 1.76 log units) in resistant strains with a suppressed SOS response. This effect was evident even after short periods (60 min) of exposure. Suppression of the SOS response reverses antimicrobial resistance across a range of E. coli phenotypes from reduced susceptibility to highly resistant, playing a significant role in increasing the in vivo efficacy.

Quantifying the contribution of four resistance mechanisms to ciprofloxacin minimum inhibitory concentration inEscherichia coli: a systematic review

“…First, the SOS response induces a higher mutation rate, making it more likely that ciprofloxacin resistance mutations will arise within a fixed population. 101 Additionally, if the SOS response is knocked out in E. coli , ciprofloxacin MIC decreases. Clinically resistant E. coli that had recA knocked out showed MIC fold decreases of 4-8.…”

“…Clinically resistant E. coli that had recA knocked out showed MIC fold decreases of 4-8. 101 Furthermore, the SOS response has been shown to induce expression of some qnr gene families, for example qnrB and qnrD . 102,103 Finally, the SOS response has been shown to promote horizontal transfer of resistance genes when E. coli is grown in the presence of ciprofloxacin.…”

The landscape of intrinsic and evolved fluoroquinolone resistance inAcinetobacter baumanniiincludes suppression of drug-induced prophage replication

“…Another major strategy for intrinsic fluoroquinolone resistance is activation of DNA damage repair pathways (14). DNA lesions caused by fluoroquinolone intoxication are processed to single-stranded DNA and subsequently induce the SOS repair response, resulting in de-repression of many genes involved in DNA recombination and repair (15).…”

“…DNA lesions caused by fluoroquinolone intoxication are processed to single-stranded DNA and subsequently induce the SOS repair response, resulting in de-repression of many genes involved in DNA recombination and repair (15). Knockout mutations in a variety of DNA repair genes result in increased fluoroquinolone susceptibility in several species (14-24). In certain cases, the SOS response also induces mobile genetic elements that carry antibiotic resistance or toxin genes, potentially influencing the spread of resistance or virulence traits (25).…”

The antioxidant drug N-acetylcysteine abolishes SOS-mediated mutagenesis produced by fluoroquinolones in bacteria

“…In particular, most studies have focused on developing SOS inhibitors that target RecA (28)(29)(30). RecA offers an appealing target because its inhibition not only reduces bacterial evolvability, but also renders bacteria more sensitive to several antibiotics (31); in some cases leading to complete reversion of antibiotic resistance (32).…”