An adaptable, fit-for-purpose screening approach with high-throughput capability to determine speed of action and stage specificity of anti-malarial compounds
- Author(s)
- Duffy, S; Sleebs, BE; Avery, VM;
- Details
- Publication Year 2024-09-12,Volume 68,Issue #10,Page e0074624
- Journal Title
- Antimicrobial Agents and Chemotherapy
- Abstract
- A revamped in vitro compound identification and activity profiling approach is required to meet the large unmet need for new anti-malarial drugs to combat parasite drug resistance. Although compound hit identification utilizing high-throughput screening of large compound libraries is well established, the ability to rapidly prioritize such large numbers for further development is limited. Determining the speed of action of anti-malarial drug candidates is a vital component of malaria drug discovery, which currently occurs predominantly in lead optimization and development. This is due in part to the capacity of current methods which have low throughput due to the complexity and labor intensity of the approaches. Here, we provide an adaptable screening paradigm utilizing automated high content imaging, including the development of an automated schizont maturation assay, which collectively can identify anti-malarial compounds, classify activity into fast and slow acting, and provide an indication of the parasite stage specificity, with high-throughput capability. By frontloading these critical biological parameters much earlier in the drug discovery pipeline, it has the potential to reduce lead compound attrition rates later in the development process. The capability of the approach in its alternative formats is demonstrated using three Medicines for Malaria Venture open access compound "boxes," namely Pathogen Box (malaria set-125 compounds), Global Health Priority Box [Malaria Box 2 (80 compounds) and zoonotic neglected diseases (80 compounds)], and the Pandemic Response Box (400 compounds). From a total of 685 compounds tested, 79 were identified as having fast ring-stage-specific activity comparable to that of artemisinin and therefore of high priority for further consideration and development.
- Publisher
- ASM
- Keywords
- Plasmodium falciparum; anti-malarial agents; drug resistance; high-throughput screening; speed of action; stage specificity
- Research Division(s)
- Chemical Biology
- PubMed ID
- 39264187
- Publisher's Version
- https://doi.org/10.1128/aac.00746-24
- Open Access at Publisher's Site
https://doi.org/10.1128/aac.00746-24- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-10-04 10:44:53
Last Modified: 2024-10-25 10:50:49