Combining Gallium Protoporphyrin and Gallium Nitrate Enhances in Vitro and in Vivo Efficacy against Pseudomonas aeruginosa: Role of Inhibition of Bacterial Antioxidant Enzymes and Resultant Increase in Cytotoxic Reactive Oxygen Species

Zachary W. Scott, Seoung Ryoung Choi, Geoffrey A. Talmon, Bradley E. Britigan, Prabagaran Narayanasamy

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Pseudomonas aeruginosa is a highly antibiotic-resistant opportunistic pathogenic bacteria that is responsible for thousands of deaths each year. Infections with P. aeruginosa disproportionately impact individuals with compromised immune systems as well as cystic fibrosis patients, where P. aeruginosa lung infection is a leading cause of morbidity and mortality. In previous work, we showed that a combination of gallium (Ga) nitrate and Ga protoporphyrin worked well in several bacterial infection models but its mechanism of action (MOA) is unknown. In the current work, we have investigated the MOA of Ga combination therapy in P. aeruginosa and its analysis in the in vivo model. In P. aeruginosa treated with Ga combination therapy, we saw a decrease in catalase and superoxide dismutase (SOD) activity, key antioxidant enzymes, which could correlate with a higher potential for oxidative stress. Consistent with this hypothesis, we found that, following combination therapy, P. aeruginosa demonstrated higher levels of reactive oxygen species, as measured using the redox-sensitive fluorescent probe, H2DCFDA. We also saw that the Ga combination therapy killed phagocytosed bacteria inside macrophages in vitro. The therapy with low dose was able to fully prevent mortality in a murine model of P. aeruginosa lung infection and also significantly reduced lung damage. These results support our previous data that Ga combination therapy acts synergistically to kill P. aeruginosa, and we now show that this may occur through increasing the organism's susceptibility to oxidative stress. Ga combination therapy also showed itself to be effective at treating infection in a murine pulmonary-infection model.

Original languageEnglish (US)
Pages (from-to)2096-2105
Number of pages10
JournalACS infectious diseases
Volume8
Issue number10
DOIs
StatePublished - Oct 14 2022

Keywords

  • Pseudomonas aeruginosa
  • ROS
  • dual Ga therapy
  • gallium
  • iron metabolism
  • superoxide dismutase

ASJC Scopus subject areas

  • Infectious Diseases

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