Reactive oxygen species play a dominant role in all pathways of rapid quinolone-mediated killing

Yuzhi Hong, Qiming Li, Qiong Gao, Jianping Xie, Haihui Huang, Karl Drlica, Xilin Zhao

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background: Quinolones have been thought to rapidly kill bacteria in two ways: (i) quinolone-topoisomerase-DNA lesions stimulate the accumulation of toxic reactive oxygen species (ROS); and (ii) the lesions directly cause lethal DNA breaks. Traditional killing assays may have underestimated the ROS contribution by overlooking the possibility that ROS continue to accumulate and kill cells on drug-free agar after quinolone removal. Methods: Quinolone-induced, ROS-mediated killing of Escherichia coli was measured by plating post-treatment samples on agar with/without anti-ROS agents. Results: When E. coli cultures were treated with ciprofloxacin or moxifloxacin in the presence of chloramphenicol (to accentuate DNA-break-mediated killing), lethal activity, revealed by plating on quinolone-free agar, was inhibited by supplementing agar with ROS-mitigating agents. Moreover, norfloxacin-mediated lethality, observed with cells suspended in saline, was blocked by inhibitors of ROS accumulation and exacerbated by a katG catalase deficiency that impairs peroxide detoxification. Unlike WT cells, the katG mutant was killed by nalidixic acid or norfloxacin with chloramphenicol present and by nalidixic or oxolinic acid with cells suspended in saline. ROS accumulated after quinolone removal with cultures either co-treated with chloramphenicol or suspended in saline. Deficiencies in recA or recB reduced the protective effects of ROS-mitigating agents, supporting the idea that repair of quinolone-mediated DNA lesions suppresses the direct lethal effects of such lesions. Conclusions: ROS are the dominant factor in all modes of quinolone-mediated lethality, as quinolone-mediated primary DNA lesions are insufficient to kill without triggering ROS accumulation. ROS-stimulating adjuvants may enhance the lethality of quinolones and perhaps other antimicrobials.

Original languageEnglish (US)
Pages (from-to)576-585
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
Volume75
Issue number3
DOIs
StatePublished - Mar 1 2020

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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