Newly identified antimicrobial activity of an 8-hydroxyquinoline-based ionophore against multidrug-resistant Enterococcus faecium and Staphylococcus aureus

Background and objectives Enterococcus faecium and Staphylococcus aureus are opportunistic bacterial pathogens with a demonstrated capacity to develop antimicrobial resistance and cause serious life-threatening infections, underscoring the urgent need for new therapeutic options. Methods Here, we have synthesized and characterized the activities of an 8-hydroxyquinoline–based ionophore antibiotic (ionophoroantibiotic; IP antibiotic), designated ‘IP-antibiotic 12.’ Results Using multidrug-resistant strains of E. faecium and S. aureus, in vitro investigations revealed that IP-antibiotic 12 exhibits bactericidal activity, demonstrates a low propensity for resistance emergence, increases the susceptibility of particular strains to select antibiotics, possesses a favorable toxicity profile, and dysregulates bacterial metal homeostasis. IP-antibiotic 12 demonstrated therapeutic efficacy against multidrug-resistant S. aureus skin infection, as a direct-acting topical antimicrobial and antibiotic adjunct when co-administered with oral linezolid. Interestingly, it was not efficacious in murine models of systemic and pulmonary infection. Conclusions These results highlight the potential of IP-antibiotic 12 as a novel therapeutic against multidrug-resistant gram-positive bacteria and provide a foundation for the development of next-generation IP-antibiotics with enhanced in vivo therapeutic efficacy.