Phosphate is a key and universal “cue” in response to which bacteria either enhance their virulence when local phosphate is scarce, or downregulate it when phosphate is adundant. Phosphate becomes depleted in the mammalian gut following physiologic stress and serves as a major trigger for colonizing bacteria to express virulence. This process cannot be reversed with oral supplementation of inorganic phosphate since it is nearly completely absorbed in the proximal small intestine. In the present study, we describe de novo synthesis of phosphorylated polyethylene glycol compounds with three defined ABA (hydrophilic/-phobic/-philic) structures: ABA-PEG10k-Pi10, ABA-PEG16k-Pi14, and ABA-PEG20k-Pi20 and linear polymer PEG20k-Pi20 absent of hydrophobic block. Polymers were tested for their efficacy against Pseudomonas aeruginosa virulence in vitro and in vivo by assessing the expression of the phosphate sensing protein PstS, the production of key virulence factor pyocyanin and Caenorhabditis elegans killing assays. Results indicate that all phosphorylated polymers suppressed phosphate sensing, virulence expression and lethality in P. aeruginosa. Among all the phosphorylated polymers, ABA-PEG20k-Pi20 displayed the greatest degree of protection against P. aeruginosa. To define the role of the hydrophobic core in ABA-PEG20k-Pi20 in the above response, we synthesized PEG20k-Pi20 in which the hydrophobic core is absent. Results indicate that the hypdrophoic core of ABA-PEG20k-Pi20 is a key structure in its protective effect against P. aeruingosa, in part, due to its ability to coat the surface of bacteria. Taken together, synthesis of novel polymers with defined structures and levels of phosphorylation may elucidate their anti-virulence action against clinically important and lethal pathogens such as P. aeruginosa.

De novo synthesis of phosphorylated tri-block copolymers with pathogen virulence suppressing properties that prevent infection-related mortality

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.