Lipophilic Ga Complex with Broad-Spectrum Antimicrobial Activity and the Ability to Overcome Gallium Resistance in both Pseudomonas aeruginosa and Staphylococcus aureus

Abstract

Antibiotic resistance (AR) necessitates the discovery of new antimicrobials with alternative mechanisms of action to those employed by conventional antibiotics. One such strategy utilizes Ga 3+ to target iron metabolism, a critical process for survival. Still, Ga-based therapies are generally ineffective against Gram-positive bacteria and promote Ga resistance. In response to these drawbacks, we report a lipophilic Ga complex, [Ga 2 L 3 (bpy) 2 ] (L = 2,2′-bis(3-hydroxy-1,4naphthoquinone; bpy = 2,2′-bipyridine)), effective against drugresistant Pseudomonas aeruginosa (DRPA; minimum inhibitory concentration, MIC = 10 μM = 14.8 μg/mL) and methicillin-resistant Staphylococcus aureus (MRSA, MIC = 100 μM = 148 μg/mL) without iron-limited conditions. Importantly, [Ga 2 L 3 (bpy) 2 ] shows noticeably delayed and decreased resistance in both MRSA and DRPA, with only 8× MIC in DRPA and none in MRSA after 30 passages. This is likely due to the dual mode of action afforded by Ga (disruption of iron metabolism) and the ligand (reactive oxygen species production). Overall, [Ga 2 L 3 (bpy) 2 ] demonstrates the utility of lipophilic metal complexes with multiple modes of action in combatting AR in Gram-positive and Gram-negative bacteria.

Bi2O3 nanoparticles exhibit potent broad-spectrum antimicrobial activity and the ability to overcome Ag-, ciprofloxacin- and meropenem-resistance in P. aeruginosa: the next silver bullet of metal antimicrobials?

“…Previous studies have described both reactive oxygen species (ROS) production and physical membrane disruption as possible mechanisms for nanomaterials, which are not shared by other conventional antibiotics. 33,34 It is important to note, however, that AgNPs only produce ROS indirectly through the interaction of Ag + ions, which are released from the oxidation of metallic Ag atoms on the surfaces of the NPs after losing the metallic bonding forces, with various enzymes and iron-sulfur clusters in bacteria. 10,35 We do not expect Bi 2 O 3 NPs to demonstrate an analogously significant release of Bi 3+ ions since Bi is already in the +3 oxidized state within the crystal structure of Bi 2 O 3 , which has a very high lattice energy.…”

Discovery of New Anti-MRSA Agents Based on Phenoxyethanol and Its Mechanism

“…Cells in each well were then treated with 100 μL of fresh medium containing varying concentrations of compound II-39 (0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25, 50, and 100 μg/mL) followed by incubation for 24 h. Afterward, the cells were incubated with 10 μL of MTT reagent at 37 °C for 2 h. Then, 100 μL of detergent reagent was added to all the wells. The plates were covered in the darkness and placed at 37 °C for 2 h. The absorbance at 570 nm was measured using a microplate reader, and the results were expressed as a percentage of viable cells. , The experiments were carried out in triplicate.…”

Gallium containing bioactive materials: A review of anticancer, antibacterial, and osteogenic properties

“…Unlike Fe 3+ , Ga 3+ cannot be reduced under physiological conditions, resulting in inhibition of several iron-dependent redox pathways. However, some mutant strains of P. aeruginosa were reported to develop resistance against gallium administrated in the form of a simple salt, such as Ga(NO 3 ) 3 [ [56] , [57] , [58] , [59] ]. The mechanism of such gallium resistance is not yet fully understood.…”