Cellular reporter screens for inhibitors of Burkholderia pseudomallei targets in Pseudomonas aeruginosa.

Transactions of the Royal Society of Tropical Medicine and Hygiene
Donald T MoirDonald E Woods

Abstract

To facilitate the discovery of new therapeutics for Burkholderia pseudomallei infections, we have developed cellular reporter screens for inhibitors of B. pseudomallei targets in the surrogate host Pseudomonas aeruginosa. Pseudomonas aeruginosa strains carrying deletions of essential genes were engineered to be dependent on the isopropyl-beta-D-thiogalactopyranoside (IPTG)-regulated expression of their B. pseudomallei orthologues on a broad-host-range plasmid. Pseudomonas aeruginosa genes which are upregulated in response to depletion of each target gene product, were fused to the Photorhabdus luminescens luxCDABE operon via pGSV3-lux-Sp(R) to generate reporter strains with increased bioluminescence upon target inhibition. A total of 11 of 19 B. pseudomallei genes complemented deletions of their orthologues in P. aeruginosa. The dependence of growth on IPTG levels varied from complete dependence (ftsQ, gyrA, glmU, secA) to slower growth in the absence of IPTG (coaD, efp, mesJ), to apparently normal growth in the absence of IPTG (ligA, lpxA, folA, ipk). Reporter screening strains have been constructed for three gene targets (gyrA, glmU, secA), and one (gyrA) has been applied to 68,000 compounds resulting in a primary hit rate of...Continue Reading

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Citations

Feb 24, 2010·Antimicrobial Agents and Chemotherapy·Daniel AielloDonald T Moir
Feb 19, 2014·Biochimica Et Biophysica Acta·Smitha Rao C VJozef Anné
Jul 15, 2015·Antimicrobial Agents and Chemotherapy·Joselynn WallaceDonald T Moir

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