Nutritional immunity and microbial infection: Development of new therapeutics

초록

Iron is an essential element for survival and metabolism for all living organisms including archaea, bacteria, and mammals. Each has evolved specialized iron uptake systems to efficiently acquire iron from the extracellular environment, competing each other for the vital nutrient. As the mammalian hosts sequester iron providing an innate defense, termed nutritional immunity, pathogenic microorganisms also have developed a number of ways to acquire, transport, and store iron for survival and virulence expression within their hosts. Especially the bacterial ferrous iron transporter protein FeoB functions as a major iron transporter in prokaryotes, making it a potential target for anti-microbial and anti-virulence therapeutics. In order to develop a novel class of anti-microbial agents targeting the bacterial iron metabolism, high-throughput screening of inhibitors against the nucleotide hydrolysis activity of FeoB based on the colorimetric and luminescence-based platforms was tested with a custom assembled library of approximately 2,000 small molecules. Two candidate molecules, GW3965?HCl and PHT-427, effectively inhibited FeoB in vitro enzyme activity, bacterial growth including Staphylococcus aureus, and its virulence factors expression. Considering the high frequency of antibiotic-resistant S. aureus, the inhibitors synergistically enhanced bacterial antibiotic susceptibility. In addition, unlike their effects on bacteria, the inhibitors did not show any toxicity on animal model systems. These results indicate that the bacterial Feo system represents a good target for anti-microbial strategies and will provide new insight for developing a next-generation antibacterial therapy.