AURANOFIN INHIBITS VIRULENCE IN PSEUDOMONAS AERUGINOSA

Abstract

Pseudomonas aeruginosa is widely attributed as the leading cause of hospital-acquired infections. Our work reveals a novel chemical compound which was found to attenuate virulence and biofilm maturation in P. aeruginosa. In this project, we initially screened for a P. aeruginosa QS inhibitors using high-throughput screening and yielded auranofin, which displayed sub-micro molar activity against LasR-mediated expression of lasB. Additionally, key virulence metabolites involving all levels of QS were also decreased on exposure to auranofin. Surprisingly, iTRAQ analysis of the P. aeruginosa proteome revealed that type III secretion system, type IV pili and biofilm maturation, in addition to inhibiting QS, were attenuated. Flow cell biofilm assays and showed that auranofin inhibits Vfr in vitro. Interestingly, auranofin also displays synergistic effects when used in combination with colistin. With a collaborator, we subsequently investigated the structure-activity relationship of auranofin by examining various analogues of auranofin for inhibition of LasB-Gfp expression as well as toxicity against several types of mammalian cells. We discovered two analogues, which were both more potent QS inhibitors, as well as less toxic to mammalian cells tested, as compared to auranofin.