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 9

Ga is effective in 2 different P. aeruginosa lung infection animal models.

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Ga is effective in 2 different P. aeruginosa lung infection animal model...
(A) Mice treated with Ga are protected from lethal P. aeruginosa pneumonia. P. aeruginosa strain PA103 (5 × 105 bacteria) was administered to mice by the intratracheal route. Mice were treated with a single dose of inhaled Ga (or vehicle alone) 3 hours after infection. Inhalation treatment was achieved by placing a 50-μl drop of concentrated Ga(NO3)3 (250 mm) or Ga-free vehicle on the nares of the mice. Because mice are obligate nose breathers, some of the drop was inhaled. Data are representative of 4 separate experiments (n = 6 mice in each group); *P < 0.005 versus vehicle control. Ga was also effective against acute pneumonia produced by strain PA01 (Supplemental Figure 10). (B) Preloading the lung with Fe blocks Ga’s antimicrobial effects. Ten microliters of 2 mM FeCl3 (or Fe-free vehicle) was administered to mice by the intratracheal route immediately prior to infection. Mice (n = 8 per group) were treated with Ga as described in A. Data are representative of 3 separate experiments; *P < 0.005 versus Fe-free control. (C) Inhaled Ga is effective in a mouse airway biofilm infection model. Infections were established as described in Methods. Mice were treated with vehicle alone or Ga (as described in A) 3 times a day for 3 days. Lungs were homogenized, and bacterial counts determined by plating (n = 4 mice per group). Data are representative of 3 separate experiments; *P < 0.005 versus vehicle control.