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