A Trojan horse strategy against pseudomonas aeruginosa involving bacterial iron acquisition pathway mediated delivery of pyochelin zingerone conjugate

Abstract

The present study was designed with an aim to synthesize Pyochelin-zingerone conjugate (PZC) 1 and to employ the conjugate for delivering zingerone 7 through bacterial iron acquisition pathway employing Trojan horse strategy. 52 strains of P. aeruginosa were screened for siderophore production, followed by optimization, purification and characterization of natural pyochelin. Chemical synthesis of nor-pyochelin 6, secondary siderophore of P. aeruginosa, and its conjugation with zingerone 7, a bio-active component of ginger was carried out. To facilitate the penetration of zingerone 7 into the bacterial cells and to improve the access of the active component to its target, the study focused towards synthesizing a conjugate possessing zingerone 7 moiety bound to nor-pyochelin 6 via a spacer arm. The approach was to exploit a Trojan Horse strategy against P. aeruginosa involving bacterial iron acquisition pathway mediated delivery of PZC 1 and was further evaluated for its anti-quorum sensing, anti-virulence and anti-biofilm potential against standard laboratory strain P. aeruginosa PAO1 along with susceptibility of organisms to innate immune responses and cell cytotoxicity. The delivery of PZC 1 through FptA receptor into the cell cytoplasm of organism blocked various virulence mechanisms and quorum sensing hence making the bacteria avirulent. The proposed approach may help in overcoming antibiotic resistance and disarming the pathogen of its virulence and may be applicable in various disease conditions caused by P. aeruginosa. newline