B-177. Inhibition of Virulence by the Interruption of Bacterial Signaling Pathways

D. A. Rasko1, C. G. Moreira1, S. Flickinger1, D. Li1, J. Ritchie2, M. Waldor2, N. Williams1, R. Taussig1, C. Mischnoff1, M. Roth1, D. T. Hughes1, J. F. Huntley1, J. R. Falck1, V. Sperandio1;
1Univ. of Texas Southwestern Med. Ctr., Dallas, TX, 2Channing Lab., Brigham and Women’s Hosp., Harvard Univ., Boston, MA.

The worldwide challenge of antimicrobial resistance and the paucity of novel antimicrobial therapies underscore the urgent need for innovative therapeutics. In recent years, it has been demonstrated that multiple bacterial pathogens exploit cell-to-cell signaling between the microbial flora and the host to activate virulence and sense the local environment. The ubiquitous nature of these signaling pathways makes them attractive therapeutic targets. Screening of a small molecule library at UTSW identified one lead compound, LED209, which can interfere with bacterial signaling and inhibit virulence of enterohemorrhagic E. coli (EHEC) in vitro and in vivo. Using quantitative RT-PCR and fluorescent actin staining we can demonstrate that LED209 decreases the expression of virulence genes and leads to the attenuation of the formation of attaching and effacing lesions by EHEC. We have extended these initial findings in EHEC to the systemic pathogens Salmonella typhimurium and Francisella tularensis and in both additional cases LED209 was an effective inhibitor of virulence factors in vitro as well as in vivo using appropriate animal models. Further studies on refining the LED209 structure and activity for treatment of bacterial infections are underway. The data taken together, suggest that LED209 and derivatives constitute a group of novel broad-spectrum therapeutics that can treat bacterial mediated disease and represent proof in principle experiments that inhibitors of cell-to-cell signaling are viable therapeutics.