Four Zn(II) complexes containing a pyridyl triazine core (L1 = 3-(2-pyridyl)-5,6-di(2-furyl)-1,2,4-triazine-5′,5″-disulfonic acid disodium salt and L2 = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine-4′,4″-disulfonic acid sodium salt) were synthesized, and their chemical formulas were finalized as [Zn(L1)Cl₂]·5H₂O·ZnCl₂ (1), [Zn(L1)₂Cl₂]·4H₂O·2CH₃OH (2), [Zn(L2)Cl₂]·3H₂O·CH₃OH (3), and [Zn(L2)₂Cl₂] (4). The synthesized complexes are water soluble, making them good candidates for biological applications. All four complexes have been characterized by elemental analysis and ¹H NMR, IR, and UV-Vis spectroscopy. The IR stretching frequency of N=N and C=N bonds of complexes 1–4 have shifted to lower frequencies in comparison with free ligands, and a bathochromic shift was observed in UV-Vis spectra of all four complexes. The binding studies of ligands and complexes 1–4 with bovine serum albumin (BSA) resulted binding constants (K_b) of 3.09 × 10⁴ M⁻¹, 12.30 × 10⁴ M⁻¹, and 16.84 × 10⁴ M⁻¹ for ferene, complex 1, and complex 2, respectively, indicating potent serum distribution via albumins.

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).

Antimicrobial resistance is a persistent threat to global public health. In order to combat the spread of pathogenic bacteria, numerous antimicrobial materials have been incorporated into wound dressings and medical devices such as implants and catheters. The most frequently utilized of these materials are Ag-salts and Ag-nanoparticles (AgNPs) due to their low minimum inhibitory concentrations (MICs) against common Gram-negative pathogenic bacteria such as P. aeruginosa. However, such Ag-based materials are limited to treating Gram-negative bacteria and prone to generating Ag-resistant phenotypes after only 7 consecutive exposures to these materials at a sub-inhibitory concentration. Here, we demonstrate α-Bi₂O₃ NPs as potential replacements for such materials, i.e., α-Bi₂O₃ NPs that exhibit potent broad-spectrum antibacterial activity (MIC = 0.75 μg mL⁻¹ against P. aeruginosa; MIC = 2.5 μg mL⁻¹ against S. aureus). Furthermore, these NPs are effective against Ag-resistant and carbapenem-resistant bacteria (MICs = 1.0 μg mL⁻¹ and 1.25 μg mL⁻¹, respectively) and also show a synergistic effect with meropenem (mero) in P. aeruginosa bacteria, allowing for the use of meropenem with smaller therapeutic doses (fractional inhibitory concentration = 0.45). Finally, unlike other materials that have been explored as effective antimicrobials, α-Bi₂O₃ NPs do not contribute to the development of Bi-resistant phenotypes after 30 passages of consecutive exposure to a sub-lethal dose of such NPs. Our results demonstrate that Bi-based materials represent a critical tool against multidrug resistant bacteria and require greater attention within the community. We anticipate this study to inspire broader investigation into the use of other metal oxides as antimicrobial materials, particularly those that limit the development of resistant phenotypes.

Iron—a double-edged sword in biology! The naturally-occuring lipophilic Fe(iii)-chelator hinokitiol allows for harnessing dysregulated iron uptake to kill Staphylococcus aureus bacteria.

Although iron is essential for all forms of life, it is also potentially toxic to cells as the increased and unregulated iron uptake can catalyze the Fenton reaction to produce reactive oxygen species (ROS), leading to lipid peroxidation of membranes, oxidation of proteins, cleavage of DNA and even activation of apoptotic cell death pathways. We demonstrate that Fe(hinok)₃ (hinok = 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one), a neutral Fe(III) complex with high lipophilicity is capable of bypassing the regulation of iron trafficking to disrupt cellular iron homeostasis; thus, harnessing remarkable anticancer activity against a panel of five different cell lines, including Pt-sensitive ovarian cancer cells (A2780; IC₅₀ = 2.05 ± 0.90 μM or 1.20 μg/mL), Pt-resistant ovarian cancer cells (A2780cis; IC₅₀ = 0.92 ± 0.73 μM or 0.50 μg/mL), ovarian cancer cells (SKOV-3; IC₅₀ = 1.23 ± 0.01 μM or 0.67 μg/mL), breast cancer cells (MDA-MB-231; IC₅₀ = 3.83 ± 0.12 μM or 2.0 μg/mL) and lung cancer cells (A549; IC₅₀ = 1.50 ± 0.32 μM or 0.82 μg/mL). Of great significance is that Fe(hinok)₃ exhibits unusual selectivity toward the normal HEK293 cells and the ability to overcome the Pt resistance in the Pt-resistant mutant ovarian cancer cells of A2780cis.