CRISPRi screen identifies FprB as a synergistic target for gallium therapy in Pseudomonas aeruginosa

Yu Zhang, Tingting Zhang, Xue Xiao, Yejun Wang, Adam Kawalek, Jinzhao Ou, Anmin Ren, Wenhao Sun, Vincent Bakker, Yujie Liu, Yuelong Li, Liang Yang, Liang Ye, Ning Jia, Jan-Willem Veening and Xue Liu ()
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Yu Zhang: Shenzhen University Medical School
Tingting Zhang: Shenzhen University Medical School
Xue Xiao: Shenzhen University Medical School
Yejun Wang: Shenzhen University Medical School
Adam Kawalek: Polish Academy of Sciences
Jinzhao Ou: Shenzhen University Medical School
Anmin Ren: Southern University of Science and Technology
Wenhao Sun: Shenzhen University Medical School
Vincent Bakker: University of Lausanne
Yujie Liu: Icahn School of Medicine at Mount Sinai
Yuelong Li: Southern University of Science and Technology
Liang Yang: Southern University of Science and Technology
Liang Ye: Shenzhen University Medical School
Ning Jia: Southern University of Science and Technology
Jan-Willem Veening: University of Lausanne
Xue Liu: Shenzhen University Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract With the rise of antibiotic-resistant bacteria, non-antibiotic therapies like gallium gain increasing attention. Intravenous gallium nitrate is under Phase II clinical trials to treat chronic Pseudomonas aeruginosa infections in cystic fibrosis patients. However, its clinical efficacy is constrained by the achievable peak concentration in human tissue. To address this limitation, we apply a genome-wide CRISPR interference approach (CRISPRi-seq) to identify potential synergistic targets with gallium. We classify the essential genes by response time and growth reduction, pinpointing the most vulnerable therapeutic targets in this species. In addition, we identify a highly conserved gene, fprB, encoding a ferredoxin-NADP⁺ reductase, whose deletion sensitizes P. aeruginosa to gallium, lowering its MIC by 32-fold and shifting mode of action from bacteriostatic to bactericidal. Further investigation reveals that FprB plays a critical role in modulating oxidative stress induced by gallium, via control of iron homeostasis and reactive oxygen species accumulation. Deleting fprB enhances gallium’s efficacy against biofilm formation and improves outcomes in a murine lung infection model of P. aeruginosa, suggesting FprB is a promising drug target in combination with gallium. Overall, our data show CRISPRi-seq as a powerful tool for systematic genetic analysis of P. aeruginosa, advancing the identification of novel therapeutic targets.

Date: 2025
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DOI: 10.1038/s41467-025-61208-z

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