Targeting the PlsX/Y pathway for novel antimicrobials

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In an effort to develop new targets for antibacterial drug discovery, we recently discovered that Gram positive bacteria use a unique and essential pathway to synthesize their membrane phospholipids mediated by two gene products, PlsX and PlsY. This pathway generates a unique acyl-phosphate intermediate via PlsX that is then utilized as a substrate for PlsY. PlsY is an essential acyltransferase and there are no mammalian homologs. Using a bioisosteric approach we designed a number of nonhydrolyzable mimics of the acyl-phosphate intermediate. When tested against a panel of representative gram positive pathogens these compounds showed only modest antimicrobial activity, with the exception of B. anthracis (Sterne strain) that was potently inhibited. To confirm this result we then tested these compounds against a panel of virulent B. anthracis strains, all of which were highly sensitive to our best inhibitors yielding comparable MIC activity to existing antibiotics. We believe that this is an ideal starting point for the development of selective B. anthracis inhibitors, which will be explored in this grant. This study has 3 specific aims: (i) To synthesize an expanded set of inhibitors and to optimize the lead compounds with respect to anti-anthracis activity and for potential oral bioavailability; (ii) to biochemically evaluate the inhibition of the B. anthracis PlsY enzymes by the newly synthesized inhibitors; (iii) To perform a microbiological assessment on the emerging lead compounds, including testing for anti-B. anthracis activity. The end point of our studies will produce a better understanding of this important biological pathway and determine whether it is a suitable target for antibacterial drug discovery.