The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity
Yukihiro Kaneko, … , Bradley E. Britigan, Pradeep K. Singh
Yukihiro Kaneko, … , Bradley E. Britigan, Pradeep K. Singh
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):877-888. https://doi.org/10.1172/JCI30783.
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Research Article Infectious disease

The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity

Abstract

A novel antiinfective approach is to exploit stresses already imposed on invading organisms by the in vivo environment. Fe metabolism is a key vulnerability of infecting bacteria because organisms require Fe for growth, and it is critical in the pathogenesis of infections. Furthermore, humans have evolved potent Fe-withholding mechanisms that can block acute infection, prevent biofilm formation leading to chronic infection, and starve bacteria that succeed in infecting the host. Here we investigate a “Trojan horse” strategy that uses the transition metal gallium to disrupt bacterial Fe metabolism and exploit the Fe stress of in vivo environments. Due to its chemical similarity to Fe, Ga can substitute for Fe in many biologic systems and inhibit Fe-dependent processes. We found that Ga inhibits Pseudomonas aeruginosa growth and biofilm formation and kills planktonic and biofilm bacteria in vitro. Ga works in part by decreasing bacterial Fe uptake and by interfering with Fe signaling by the transcriptional regulator pvdS. We also show that Ga is effective in 2 murine lung infection models. These data, along with the fact that Ga is FDA approved (for i.v. administration) and there is the dearth of new antibiotics in development, make Ga a potentially promising new therapeutic for P. aeruginosa infections.

Authors

Yukihiro Kaneko, Matthew Thoendel, Oyebode Olakanmi, Bradley E. Britigan, Pradeep K. Singh

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Figure 1

Effect of Ga on P. aeruginosa growth.

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Effect of Ga on P. aeruginosa growth. (A) Ga(NO3)3 inhib...
(A) Ga(NO3)3 inhibits P. aeruginosa growth in a concentration-dependent manner. Experiments were performed in biofilm medium at 37°C, and data are the mean of 4 experiments; error bars indicate SEM. (B) Ga kills P. aeruginosa. Bacteria were grown in TSB to stationary phase and incubated with indicated concentrations of Ga(NO3)3 for 24 hours. Cells were then pelleted and washed 3 times to remove Ga, and viable bacteria were enumerated by plate counting. Data are the mean of 3 experiments; error bars indicate SEM; *P < 0.001 versus the untreated control. (C) The addition of Fe (FeCl3) diminishes Ga’s growth-inhibitory effects. Data are the mean of 3 experiments; error bars indicate SEM. (D) Ga sensitivity of P. aeruginosa isolates from chronically infected CF patients. Clinical isolates and PA01 bacteria were grown for 24 hours at 37°C in BM2 succinate medium with 0.1% casamino amino acids with increasing (2-fold) concentrations of Ga(NO3)3. The IC90 of PA01 (determined by measuring OD600) was 10 μM Ga in this medium. Isolates represented by points lying above the dotted line were more resistant than PA01. Data are mean of 2 measurements for each isolate.