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<p>Gonorrhoea is a major sexually transmitted infection and the emergence of multidrug-resistant <i>Neisseria gonorrhoeae</i> poses a global health threat. To identify candidate antibiotics against <i>N. gonorrhoeae</i>, we screened <i>Pseudomonas aeruginosa</i>-derived secondary metabolites and found that 2-nonyl-4-quinolone <i>N</i>-oxide (NQNO) abrogated growth of <i>N. gonorrhoeae</i> in vitro. NQNO did not impair growth of commensal <i>Neisseriae</i>, vaginal lactobacilli or viability of human cells. Mechanistically, NQNO disrupted the electron transport chain, depleted ATP and NADH levels and increased oxidative stress. This triggered activation of a toxin–antitoxin system, release of the endogenous Zeta1 toxin and bacterial death. In a mouse model of infection, topical application of NQNO prevented colonization by <i>N. gonorrhoeae</i>. Chemical modification yielded 3-methyl NQNO, which exhibited nanomolar potency against multidrug-resistant strains, lack of resistance development and significantly reduced pathogen numbers during experimental infection of mice. These findings show the potential for selective killing of bacterial pathogens such as multidrug-resistant <i>N. gonorrrhoeae</i> through activation of endogenous toxins.</p>

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A quinolone N-oxide antibiotic selectively targets Neisseria gonorrhoeae via its toxin–antitoxin system

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月2日

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  • Ann-Kathrin Mix,
  • Thi Hong Nhung Nguyen,
  • Tamara Schuhmacher,
  • Dávid Szamosvári,
  • Petra Muenzner,
  • Paula Haas,
  • Lydia Heeb,
  • Haleluya T. Wami,
  • Ulrich Dobrindt,
  • Yasar Özge Delikkafa,
  • Thomas U. Mayer,
  • Thomas Böttcher,
  • Christof R. Hauck

摘要

Gonorrhoea is a major sexually transmitted infection and the emergence of multidrug-resistant Neisseria gonorrhoeae poses a global health threat. To identify candidate antibiotics against N. gonorrhoeae, we screened Pseudomonas aeruginosa-derived secondary metabolites and found that 2-nonyl-4-quinolone N-oxide (NQNO) abrogated growth of N. gonorrhoeae in vitro. NQNO did not impair growth of commensal Neisseriae, vaginal lactobacilli or viability of human cells. Mechanistically, NQNO disrupted the electron transport chain, depleted ATP and NADH levels and increased oxidative stress. This triggered activation of a toxin–antitoxin system, release of the endogenous Zeta1 toxin and bacterial death. In a mouse model of infection, topical application of NQNO prevented colonization by N. gonorrhoeae. Chemical modification yielded 3-methyl NQNO, which exhibited nanomolar potency against multidrug-resistant strains, lack of resistance development and significantly reduced pathogen numbers during experimental infection of mice. These findings show the potential for selective killing of bacterial pathogens such as multidrug-resistant N. gonorrrhoeae through activation of endogenous toxins.