An iron-chelating sulfonamide identified from <i>Drosophila</i>-based screening for antipathogenic discovery

We exploited bacterial infection assays using the fruit fly <i>Drosophila melanogaster</i> to identify anti-infective compounds that abrogate the pathological consequences in the infected hosts. Here, we demonstrated that a pyridine-3-<i>N</i>-sulfonylpiperidine derivative (<b>4a</b>) protects <i>Drosophila</i> from the acute infections caused by bacterial pathogens including <i>Pseudomonas aeruginosa</i>. <b>4a</b> did not inhibit the growth of <i>P. aeruginosa</i> in vitro, but inhibited the production of secreted toxins such as pyocyanin and hydrogen cyanide, while enhancing the production of pyoverdine and pyochelin, indicative of iron deprivation. Based on its catechol moiety, <b>4a</b> displayed iron-chelating activity in vitro toward both iron (II) and iron (III), more efficiently than the approved iron-chelating drugs such as deferoxamine and deferiprone, concomitant with more potent antibacterial efficacy in <i>Drosophila</i> infections and unique transcriptome profile. Taken together, these results delineate a <i>Drosophila</i>–based strategy to screen for antipathogenic compounds, which interfere with iron uptake crucial for bacterial virulence and survival in host tissues.