AUTHOR=Liu Chang , Cui Chenxuan , Tan Xiaoxin , Miao Junjie , Wang Wei , Ren Han , Wu Hua , Zheng Cuiying , Ren Huan , Kang Weijun 

TITLE=pH-mediated potentiation of gallium nitrate against Pseudomonas aeruginosa

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1464719

DOI=10.3389/fmicb.2024.1464719

ISSN=1664-302X

ABSTRACT=<p>The emergence of multidrug-resistant <italic>Pseudomonas aeruginosa</italic> isolates is a growing concern for public health, necessitating new therapeutic strategies. Gallium nitrate [Ga(NO<sub>3</sub>)<sub>3</sub>], a medication for cancer-related hypercalcemia, has attracted great attention due to its ability to inhibit <italic>P. aeruginosa</italic> growth and biofilm formation by disrupting iron metabolism. However, the antibacterial efficacy of Ga(NO<sub>3</sub>)<sub>3</sub> is not always satisfactory. It is imperative to investigate the factors that affect the bactericidal effects of Ga(NO<sub>3</sub>)<sub>3</sub> and to identify new ways to enhance its efficacy. This study focused on the impact of pH on <italic>P. aeruginosa</italic> resistance to Ga(NO<sub>3</sub>)<sub>3</sub>, along with the underlying mechanism. The results indicate that acidic conditions could increase the effectiveness of Ga(NO<sub>3</sub>)<sub>3</sub> against <italic>P. aeruginosa</italic> by promoting the production of pyochelin and gallium uptake. Subsequently, using glutamic acid, a clinically compatible acidic amino acid, the pH was significantly lowered and enhanced the bactericidal and inhibitory efficacy of Ga(NO<sub>3</sub>)<sub>3</sub> against biofilm formation by <italic>P. aeruginosa</italic>, including a reference strain PA14 and several multidrug-resistant clinical isolates. Furthermore, we used an abscess mouse model to evaluate this combination <italic>in vivo</italic>; the results show that the combination of glutamic acid and Ga(NO<sub>3</sub>)<sub>3</sub> significantly improved <italic>P. aeruginosa</italic> clearance. Overall, the present study demonstrates that acidic conditions can increase the sensitivity of <italic>P. aeruginosa</italic> to Ga(NO<sub>3</sub>)<sub>3</sub>. Combining glutamic acid and Ga(NO<sub>3</sub>)<sub>3</sub> is a potential strategy for the treatment of <italic>P. aeruginosa</italic> infections.</p>