Discovery of Ionophoroantibiotics as a New Antibiotic Class Targeting Metal Homeostasis in Multidrug-Resistant <i>Neisseria gonorrhoeae</i>

The rise of multidrug-resistant (MDR) <i>Neisseria gonorrhoeae</i> is a growing health concern. New treatments are urgently needed as resistance to last-line antibiotics increases. The zinc ionophore, PBT2, has previously been shown to facilitate zinc uptake in bacteria and restore susceptibility to existing antibiotics in combination therapies. In contrast, we demonstrate that PBT2 alone is sufficient to inhibit the growth of <i>N. gonorrhoeae</i>. Guided by this finding, we synthesized a series of 8-hydroxyquinoline-based new chemical entities, herein termed a "ionophoroantibiotics (IP-antibiotics)." These compounds displayed potent activity against MDR <i>N. gonorrhoeae</i>, with several exhibiting greater efficacy than PBT2. Proteomic profiling studies suggested IP-antibiotics disrupt metal and phosphate metabolism in <i>N. gonorrhoeae</i>, upregulating iron transport and downregulating phosphate pathways. PBT2 broadly affects metal and metabolic proteins, whereas the new compounds act more selectively. This distinct mode of action circumvents established resistance mechanisms and targets key bacterial vulnerabilities. Collectively, these findings identify IP-antibiotics as a promising new class of antibiotics for the treatment of MDR <i>N. gonorrhoeae</i>.