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

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.