Establishment of a novel whole animal HTS technology platform for melioidosis drug discovery
Umayal Lakshmanan, Amelia Yap, Justina Fulwood
1Experimental Therapeutics Centre, A*STAR (Agency for Science, Technology and Research), Singapore. hflotow@d3.a-star.edu.sg.
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.
Insights
A new whole-animal infection model using Caenorhabditis elegans was developed to screen for melioidosis treatments. This high-throughput screening assay identified novel antibacterial compounds for potential therapeutic use against Burkholderia pseudomallei.
Area of Science:
- Infectious Diseases
- Microbiology
- Drug Discovery
Background:
- Melioidosis, caused by Burkholderia pseudomallei, is an emerging infectious disease with high mortality.
- Burkholderia pseudomallei exhibits increasing antibiotic resistance, necessitating novel treatment strategies.
Purpose of the Study:
- To establish a high-throughput screening (HTS) assay for identifying antibacterial compounds against melioidosis.
- To develop a surrogate whole-animal infection model for melioidosis research.
Main Methods:
- Utilized Caenorhabditis elegans infected with Burkholderia thailandensis as a model organism.
- Developed and optimized a fluorescence-based, whole-animal HTS assay compatible with automated screening platforms.
- Screened over 300,000 small molecules from a compound library.
Main Results:
- Successfully established and validated a biologically relevant HTS assay for antibacterial compound screening.
- Identified and are currently characterizing potential hit compounds from the library screen.
- The assay platform is suitable for large-scale screening of antibacterial agents.
Conclusions:
- A novel HTS assay platform has been established for melioidosis research.
- This platform facilitates the identification of new antibacterial compounds for treating melioidosis.
- The developed assay technology holds promise for discovering novel therapeutic agents against drug-resistant pathogens.
