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

Mix, Ann-Kathrin; Nguyen, Thi Hong Nhung; Schuhmacher, Tamara; Szamosvari, David; Muenzner, Petra; Haas, Paula; Heeb, Lydia; Wami, Haleluya T.; Dobrindt, Ulrich; Delikkafa, Yasar Oezge; Mayer, Thomas U.; Boettcher, Thomas; Hauck, Christof R.

Research article (journal) | Peer reviewed

Abstract

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.

Details about the publication

JournalNature Microbiology
Volume10
Issue4
Page range939-957
StatusPublished
Release year2025 (02/04/2025)
Language in which the publication is writtenEnglish
DOI10.1038/s41564-025-01968-y
Link to the full texthttps://api.elsevier.com/content/abstract/scopus_id/105001654362
KeywordsNeisseria gonorrhoeae; Animals; Anti-Bacterial Agents; Mice; Humans; Gonorrhea; Quinolones; Female; Toxin-Antitoxin Systems; Pseudomonas aeruginosa; Disease Models, Animal; Oxidative Stress; Bacterial Toxins; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial; Adenosine Triphosphate

Authors from the University of Münster

Dobrindt, Ulrich
Institute of Hygiene