Accelerating\nAntimalarial Drug Discovery with a New\nHigh-Throughput Screen for Fast-Killing Compounds

The urgent need for rapidly acting compounds in the development\nof antimalarial drugs underscores the significance of such compounds\nin overcoming resistance issues and improving patient adherence to\nantimalarial treatments. The present study introduces a high-throughput\nscreening (HTS) approach using 1536-well plates, employing Plasmodium falciparum lactate dehydrogenase (PfLDH)\ncombined with nitroreductase (NTR) and fluorescent probes to evaluate\ninhibition of the growth of the asexual blood stage of malaria parasites.\nThis method was adapted to efficiently assess the speed of action\nprofiling (SAP) in a 384-well plate format, streamlining the traditionally\ntime-consuming screening process. By successfully screening numerous\ncompounds, this approach identified fast-killing hits early in the\nscreening process, addressing challenges associated with artemisinin-based\ncombination therapies. The high-throughput SAP method is expected\nto be of value in continuously monitoring fast-killing properties\nduring structure–activity relationship studies, expediting\nthe identification and development of novel, rapidly acting antimalarial\ndrugs within phenotypic drug discovery campaigns.