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 Mn²⁺, Zn^2+, and Cu²⁺ 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).

Background/Objectives: The widespread use of mupirocin and fusidic acid for the treatment and decolonization of Staphylococcus aureus (SA) skin infections has led to a rapid emergence of resistant strains, limiting the effectiveness of the few topical agents currently available for clinical use. Methods: In this study, we evaluate Fe(tropo)₃, a neutral and lipophilic iron(III)–tropolone complex, as a non-antibiotic topical antimicrobial candidate for the management of drug-resistant SA skin and soft tissue infections. Results: Fe(tropo)₃ exhibits potent in vitro activity against methicillin-susceptible SA, methicillin-resistant SA (MRSA), vancomycin-intermediate SA, and strains with high-level resistance to mupirocin and fusidate, with minimum inhibitory concentrations of 2 µg/mL across all tested isolates. The compound effectively penetrates bacterial cells, induces intracellular iron accumulation, and triggers dose-dependent reactive oxygen species generation, resulting in rapid bacterial killing and significant antibiofilm activity. Importantly, Fe(tropo)₃ shows a slower development of resistance compared with ciprofloxacin and displays synergistic activity with oxacillin against MRSA. When formulated as a 1% topical ointment, Fe(tropo)₃ significantly reduces bacterial burden in a murine excisional wound infection model, achieving a 98% ± 1% reduction in SA load without detectable hemolysis or skin irritation. Conclusions: These pilot study results support Fe(tropo)₃ as a clinically relevant, mechanism-distinct topical antimicrobial with potential utility in settings where resistance to existing topical antibiotics compromises standard care.

Ga(III) can mimic Fe(III) in the biological system due to its similarities in charge and ionic radius to those of Fe(III) and can exhibit antimicrobial activity by disrupting the acquisition and metabolism of Fe in bacterial cells. For example, Ga(NO₃)₃ has been proven to be effective in treating chronic lung infections by Pseudomonas aeruginosa (P. aeruginosa) in cystic fibrosis patients in a recent phase II clinical trial. However, Ga(NO₃)₃ is an ionic compound that can hydrolyze to form insoluble hydroxides at physiological pH, which not only reduces its bioavailability but also causes potential renal toxicity when it is used as a systemic drug. Although complexion with suitable chelating agents has offered a varying degree of success in alleviating the hydrolysis of Ga(III), the use of nanotechnology to deliver this metallic ion should constitute an ultimate solution to all the above-mentioned problems. Thus far, the development of Ga-based nanomaterials as metalloantibiotics is an underexploited area of research. We have developed two different synthetic routes for the preparation of biocompatible Ga₂(HPO₄)₃ NPs and shown that both the PVP- or PEG-coated Ga₂(HPO₄)₃ NPs exhibit potent antimicrobial activity against P. aeruginosa. More importantly, such polymer-coated NPs do not show any sign of Ga-resistant phenotype development after 30 passes, in sharp contrast to Ga(NO₃)_3, which can rapidly develop Ga-resistant phenotypes of P. aeruginosa, indicating the potential of using Ga₂(HPO₄)₃ NPs a new antimicrobial agent in place of Ga(NO₃)₃.

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a critical public health threat, particularly in hospital environments where treatment options are limited. Drug repurposing offers a rapid and cost-effective strategy to address antimicrobial resistance. This study evaluates KP46 (tris(8-quinolinolato)gallium(III)), an orally bioavailable gallium-based anticancer agent, for its antimicrobial potential against CRAB. Methods: KP46 was synthesized and characterized using spectroscopic and crystallographic techniques. Its antibacterial activity was assessed against planktonic and biofilm-associated CRAB strains, including multidrug-resistant clinical isolates. Mechanistic studies included intracellular reactive oxygen species (ROS) quantification, membrane integrity assays, and resistance development profiling. Results: KP46 exhibited potent antibacterial activity against both susceptible and carbapenem-resistant A. baumannii strains. It inhibited planktonic growth and disrupted early biofilm formation. KP46 induced intracellular oxidative stress, leading to membrane damage and cell death. Resistance development was significantly slower compared to meropenem, and KP46 retained efficacy against meropenem-resistant isolates. Conclusions: KP46 demonstrates dual-action antimicrobial activity and a low propensity for resistance development, positioning it as a promising candidate for repurposing against CRAB infections. These findings support further preclinical evaluation of KP46 as an orally active therapeutic agent targeting both planktonic and biofilm-associated bacterial populations. resistance development and retained efficacy against meropenem-resistant strains.

Gallium-based antimicrobials have historically shown their strongest activity against Gram-negative pathogens, particularly P. aeruginosa, while exhibiting limited efficacy against S. aureus. Here, we demonstrate that ligand design can profoundly alter the antibacterial spectrum of gallium complexes. Among six structurally distinct Ga(III) complexes evaluated, gallium tris(8-hydroxyquinolinate), Ga(8HQ)₃, emerged as the only compound displaying potent anti-staphylococcal activity. Ga(8HQ)₃ exhibited low MIC values (2.5-5.0 μg/mL) against methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), and multiple clinical isolates, and demonstrated rapid bactericidal activity with MBC/MIC ratios ≤2. The complex also effectively inhibited MRSA biofilm formation and restored susceptibility of a mupirocin-resistant MRSA strain, reducing the mupirocin MIC by 64-fold. The crystallographic, computational, and biological data together support a mechanistic model in which ligand coordination enhances intracellular gallium delivery. Consistent with this model, Ga(8HQ)₃ produced substantially greater intracellular gallium accumulation than gallium nitrate, accompanied by increased oxidative stress and membrane permeabilization. In serial-passage studies, Ga(8HQ)₃ exhibited a low propensity for resistance development and retained activity against mupirocin-resistant MRSA, indicating minimal cross-resistance.,Collectively, these findings demonstrate that rational ligand selection can reprogram the biological behavior of gallium complexes, transforming a traditionally anti-Gram-negative metallodrug platform into a potent anti-staphylococcal agent and identifying Ga(8HQ)₃ as a promising candidate for treating drug-resistant and biofilm-associated S. aureus infections.

Antimicrobial resistance (AMR) is an increasing global health threat that underscores the urgent need for antimicrobial agents with mechanisms of action distinct from those of conventional antibiotics. Gallium (Ga) has emerged as a promising metal-based antimicrobial owing to the chemical similarity of Ga(III) to Fe(III), which enables it to interfere with bacterial iron acquisition and utilization. In contrast to Fe(III), Ga(III) is redox-inactive under physiological conditions and cannot support the redox reactions required for many iron-dependent cellular processes, thereby disrupting bacterial metabolism. This review highlights recent advances in gallium-based antimicrobial strategies, with particular emphasis on the role of ligand coordination in modulating the antibacterial activity of Ga(III) against drug-resistant pathogens. Emerging evidence indicates that coordination with lipophilic ligands can enhance the cellular update and accumulation of Ga(III) and may confer additional antibacterial effects beyond Fe(III) mimicry alone. These findings suggest that ligand design is a key strategy for tuning the physicochemical properties and antimicrobial activity of gallium complexes. Rational development of ligand-coordinated Ga(III) complexes may therefore provide new therapeutic approaches for combating multidrug-resistant bacterial infections.