pH-mediated potentiation of gallium nitrate against Pseudomonas aeruginosa

The emergence of multidrug-resistant Pseudomonas aeruginosa isolates is a growing concern for public health, necessitating new therapeutic strategies. Gallium nitrate [Ga(NO₃)₃], a medication for cancer-related hypercalcemia, has attracted great attention due to its ability to inhibit P. aeruginosa growth and biofilm formation by disrupting iron metabolism. However, the antibacterial efficacy of Ga(NO₃)₃ is not always satisfactory. It is imperative to investigate the factors that affect the bactericidal effects of Ga(NO₃)₃ and to identify new ways to enhance its efficacy. This study focused on the impact of pH on P. aeruginosa resistance to Ga(NO₃)₃, along with the underlying mechanism. The results indicate that acidic conditions could increase the effectiveness of Ga(NO₃)₃ against P. aeruginosa 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(NO₃)₃ against biofilm formation by P. aeruginosa, including a reference strain PA14 and several multidrug-resistant clinical isolates. Furthermore, we used an abscess mouse model to evaluate this combination in vivo; the results show that the combination of glutamic acid and Ga(NO₃)₃ significantly improved P. aeruginosa clearance. Overall, the present study demonstrates that acidic conditions can increase the sensitivity of P. aeruginosa to Ga(NO₃)₃. Combining glutamic acid and Ga(NO₃)₃ is a potential strategy for the treatment of P. aeruginosa infections.