Bacteriostatic Activity of Gallium Acetate

gallium acetate is a yellowish-white crystalline salt and is a popular precursor to ultra-pure compounds, catalysts and nanoscale materials. The compound exhibits strong electrostatic and magnetic interactions, making it a good candidate for applications in biotechnology and other fields that require multi-functional materials.

Metal-based antimicrobials have received renewed interest in the era of antibiotic resistance and drying pipelines. We have previously shown that gallium disrupts bacterial iron metabolism, and its bacteriostatic effect is potent against Pseudomonas aeruginosa persisters as demonstrated in mammalian cell infection and murine skin infection models. However, the mechanism behind these effects remains largely unknown.

Here we show that the central carbon metabolite acetate significantly enhances the bacteriostatic activity of gallium against P. aeruginosa, and this enhancement correlates with Ga(iii) uptake by the bacteria. In addition, acetate directly promotes the transcription of Ga(iii)-bound genes, which attenuates bacterial virulence in A549 cells and mouse skin wound infections.

A combination treatment of Ga(iii) and acetate further attenuates bacterial loads in A549 cells, while acetate alone significantly reduces bacterial counts in mice infected with 5 106 CFU of P. aeruginosa in an excisional skin wound infection model. A cellular transcriptome analysis and a metabolomics study reveal that the combined Ga-acetate treatment also enhances phagocytosis and apoptosis, and attenuates mRNA expression of Ga(iii)-bound proteins such as PaRpoB/C (Figs. S2B+ and S11+). We confirmed this finding by using competitive Gallium-based Immobilized Metal Affinity Chromatography to identify Ga-binding proteins in P. aeruginosa lysates, where pre-treatment of the bacterium with Ga(NO3)3 led to pre-saturation of actual binding sites and reduced abundance in the eluted protein fraction.