Harnessing the Dual Antimicrobial Mechanism of Action with Fe(8-Hydroxyquinoline)(3) to Develop a Topical Ointment for Mupirocin-Resistant MRSA Infections

8-Hydroxyquinoline (8-hq) exhibits potent antimicrobial activity against Staphylococcus aureus (SA) bacteria with MIC = 16.0–32.0 µM owing to its ability to chelate metal ions such as Mn(2+), Zn(2+,) and Cu(2+) to disrupt metal homeostasis in bacterial cells. We demonstrate that Fe(8-hq)(3), the 1:3 complex formed between Fe(III) and 8-hq, can readily transport Fe(III) across the bacterial cell membrane and deliver iron into the bacterial cell, thus, harnessing a dual antimicrobial mechanism of action that combines the bactericidal activity of iron with the metal chelating effect of 8-hq to kill bacteria. As a result, the antimicrobial potency of Fe(8-hq)(3) is significantly enhanced in comparison with 8-hq. Resistance development by SA toward Fe(8-hq)(3) is considerably delayed as compared with ciprofloxacin and 8-hq. Fe(8-hq)(3) can also overcome the 8-hq and mupirocin resistance developed in the SA mutant and MRSA mutant bacteria, respectively. Fe(8-hq)(3) can stimulate M1-like macrophage polarization of RAW 264.7 cells to kill the SA internalized in such macrophages. Fe(8-hq)(3) exhibits a synergistic effect with both ciprofloxacin and imipenem, showing potential for combination therapies with topical and systemic antibiotics for more serious MRSA infections. The in vivo antimicrobial efficacy of a 2% Fe(8-hq)(3) topical ointment is confirmed by the use of a murine model with skin wound infection by bioluminescent SA with a reduction of the bacterial burden by 99 ± 0.5%, indicating that this non-antibiotic iron complex has therapeutic potential for skin and soft tissue infections (SSTIs).