(293a) Phosphorylated Amphiphilic Pegs: Next Generation Anti-Microbials

Postoperative bacterial infections can cause life-threatening complications for patients and are cost prohibitive. A wide array of bacteria has developed resistance to antibiotics, and are often ubiquitous in hospital environments. Bacterial colonies in the body signal each other to up-regulate virulence-related genes, a process that is exacerbated in phosphate-depleted environments. In order to inhibit virulence in potentially deleterious infections, we have synthesized and characterized a library of amphiphilic PEG-based polymers bearing phosphate end-groups . Exploiting a model developed in the Alverdy group which tests C. elegans worms’ mortality in the presence of the gram-negative human pathogen Pseudomonas aeruginosa, we were able to pre-screen our library for the most effective protectants. The best performing material, a PEG bearing a bisphenol moiety at its center and phosphate end-groups has been found to suppress both environmental and cell-to-cell signaling as seen by suppression of pyoverdin and pyocyanin production by  P. aeruginosa in phosphate and iron depleted environments, and by interruption of host-to-bacteria (opioid signaling) and bacteria-to-bacteria signaling (pseudomonas quinolone signaling). This polymer also inhibits biofilm production induced by bacteria. Upon inoculation of patient-derived, resistant, hospital-borne culture in a murine, surgical injury model, notably this polymer decreased mouse mortality by 80%. Physical characterization of the polymer has helped to further elucidate the in vivo mechanism, including determination of critical aggregation concentrations, the ability of the polymers to entrap hydrophobic molecules (i.e. hydrophobic bacterial signaling molecules), and the strength of interaction between these polymers and lipid rafts in the gut.