An Automated Method of Mass Drug Testing Applied to Screening for Antimalarial Activity

Abstract
An automated (robot) wet-chemistry system has been developed and is being used routinely for mass screening of candidate compounds for antimalarial activity by measuring the ability of these compounds to inhibit glucose consumption and lactic acid production by intraerythrocytic P.berghei in vitro. Drug toxicity or the degree of specific antimalarial activity is evaluated by re-testing via the automated system all drugs found active against P. berghei for ability to inhibit the glucose metabolism of Walker 256 cancer cells in ascites form. The justification for this approach to screening for antimalarials rests, in part, with the reports that intraerythrocytic P. berghei and P. knowlesi lack an active tricarboxylic acid cycle and thus rodent and primate malarial parasites probably depend upon glucose catabolism via glycolysis for essentially all of their metabolic energy. The advantages of the automated in vitro screening system include rapid drug evaluation (only 70 min are required before an ‘active’ or ‘inactive’ designation can be made on a candidate drug), high volume through-put potential (drugs are screened at a rate of one every 4 min) and a low cost per drug test. In addition, by simultaneously measuring drug interference with several metabolic activities, as attempted with the present study, one can also obtain information on the mechanism of drug action. Lastly, as demonstrated by the use of ascites tumor cells for the test of drug toxicity, the system could just as readily have been constructed with the objective of mass screening potential antineoplastic agents. In fact, the only prerequisites for screening drugs against any organism are that the organism or cell be in suspension and that the investigated metabolic activities occurring during the in vitro incubation be detectable by automated methodology.