title: Establishment of a novel whole animal HTS technology platform for melioidosis drug discovery.
abstract: Melioidosis is a serious emerging endemic infectious disease caused by Burkholderia pseudomallei, a gram-negative pathogen. Septicemic melioidosis has a mortality rate of 50% even with treatment. Like other gram-negative bacteria, B. pseudomallei is resistant to a number of antibiotics and multi-drug resistant B. pseudomallei is beginning to be encountered in hospitals. There is a clear medical need to develop new treatment options to manage this disease. We used Burkholderia thailandensis (a BSL-2 class organism) to infect Caenorhabditis elegans and set up a surrogate whole animal infection model of melioidosis that we could run in a 384 microtitre plate and establish a whole animal HTS assay. We have optimized and validated this assay in a fluorescence-based format that can be run on our automated screening platforms. This assay has now been used to screen over 300,000 compounds from our small molecule library and we are in the process of characterizing the hits obtained and select compounds for further studies. We have thus established a biologically relevant assay technology platform to screen for antibacterial compounds and used this platform to identify new compounds that may find application in treating melioidosis infections.
authors.forename: Umayal
authors.initials: U
authors.lastname: Lakshmanan
authors.forename: Amelia
authors.initials: A
authors.lastname: Yap
authors.forename: Justina
authors.initials: J
authors.lastname: Fulwood
authors.forename: Li
authors.initials: L
authors.lastname: Yichun
authors.forename: Sim Siew
authors.initials: SS
authors.lastname: Hoon
authors.forename: Jolander
authors.initials: J
authors.lastname: Lim
authors.forename: Audrey
authors.initials: A
authors.lastname: Ting
authors.forename: Xiao Hui
authors.initials: XH
authors.lastname: Sem
authors.forename: Jason F
authors.initials: JF
authors.lastname: Kreisberg
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: Gladys
authors.initials: G
authors.lastname: Tan
authors.affiliation: Experimental Therapeutics Centre, A*STAR (Agency for Science, Technology and Research), Singapore. hflotow@d3.a-star.edu.sg.
authors.forename: Horst
authors.initials: H
authors.lastname: Flotow
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D016957:Burkholderia pseudomallei / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000382:microbiology; D004195:Disease Models, Animal; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D008554:Melioidosis / Q000188:drug therapy* / Q000382:microbiology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D054852:Small Molecule Libraries