Antifolate studies. Activities of 40 potential antimalarial compounds against sensitive and chlorguanide triazine resistant strains of folate-requiring bacteria and Escherichia coli

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Abstract
As part of the search for new antimalarial drugs, a screening program was developed using sensitive and chlorguanide triazine (CGT, cycloguanil) resistant strains of the folate-requiring bacteria, Streptococcus faecium durans, Lactobacillus casei and Pediococcus cerevisiae. The activities of 40 compounds were studied against these strains and E. coli. Observations were made on the points of 50% growth inhibition, the fold increase of resistance shown to each compound by the resistant strains as compared with the parent sensitive strains, and the reversal of growth inhibition by folic acid with S. faecium and L. casei by folinic acid with P. cerevisiae and by p-aminobenzoic acid with E. coli. Comparisons were made of the activities of the test compounds with those of the standard antimalarial antifolates, CGT and pyrimethamine (PM), and the antibacterial results were compared with the activities of the compounds against Plasmodium berghei infections in the mouse and against human malaria infections where data are available. Of the 17 compounds reversed by folates, 5 had patterns of activity similar to CGT and PM in that they were most active against S. faecium and 9 compounds exhibited a different pattern, being highly active against all 4 test bacteria. This suggests that these latter compounds either have different pharmacokinetic properties or have additional modes of action. The 3 CGT-resistant organisms responded to antifolates in different ways. S. faecium (R) and P. cerevisiae (R) strains were cross resistant to 4,6-diaminotriazines, 2,4-diaminopyrimidines, 2,4-diaminoquinazolines, and active 2,4-diaminopteridines. L. casei (R) was cross resistant to the triazines but was collaterally sensitive to all the other antifolates. Most of the compounds not reversed by folates were much less inhibitory for the test organisms; they were most active against L. casei. In general, their growth inhibitory concentrations varied less for the 4 test organisms and the responses of the sensitive and CGTR strains were similar. However, there was some cross resistance to 5 compounds and some collateral sensitivity to 5 others. Comparison of the bacteriological data with the activities of the compounds against Plasmodium berghei in the mouse showed little correlation between the 2 test systems; each appears to provide independent and useful information.

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