Sulphadiazine-resistance in Plasmodium gallinaceum and its relation to other antimalarial compounds

Abstract

1. A thirty-two-fold increase in resistance to sulphadiazine has been induced in Plasmodium gallinaceum in chicks by treatment with that drug.2. No loss in resistance to sulphadiazine occurred in the resistant strain during cyclical passage through Aëdes aegypti.3. The sulphadiazine-resistant strain was resistant also to sulphathiazole, sulphanilamide and sulphapyridine, but not to mepacrine, quinine or pamaquin. An increase in sensitivity to pamaquin was observed.4. The sulphadiazine-resistant strain was resistant to paludrine and its methyl homologue M 4430.5. In strains maintained in a state of acute infection and treated with sulphadiazine, resistance to paludrine developed more rapidly than resistance to sulphadiazine, and in one strain a high degree of resistance to paludrine was obtained before any increase in resistance to sulphadiazine could be detected.6. Resistance to paludrine as induced by sulphadiazine, develops rapidly and extends at once over the full range of doses which the chick will tolerate, whereas resistance to paludrine as induced by that drug itself, develops more slowly and by stages.7. Whereas resistance to paludrine is induced readily by treatment with sulphadiazine, resistance to sulphadiazine is induced by paludrine only after treatment with high doses of the drug for a prolonged period.8. In latent infections of Plasmodium gallinaceum resistance to paludrine or sulphadiazine was not induced by sulphadiazine during the period of the experiment (49–75 days), though the aggregate dosage of drug used was much greater than that with which resistance was induced in strains maintained in an acute state.9. It is not considered probable that cross-resistance between sulphadiazine and paludrine is due to a similar mode of action of these drugs, as whereas sulphadiazine is antagonized by p-amino-benzoic acid paludrine is not.

THE MODE OF ACTION OF SULPHONAMIDES, PROGUANIL AND PYRIMETHAMINE ON PLASMODIUM GALLINACEUM

“…Rollo's strain, however, was only partially resistant, and it is possible that, with an increase in its resistance to sulphadiazine, cross-resistance to pyrimethamine would have appeared. Bishop and McConnachie (1948) reported that a proguanil-fast strain of P. gallinaceum became resistant to sulphadiazine. All other workers have found that strains made resistant to proguanil have retained their sensitivity to sulphadiazine, and Bishop (1951) was unable to confirm the earlier result.…”

“…Bishop and McConnachie (1948) reported that a proguanil-fast strain of P. gallinaceum became resistant to sulphadiazine. All other workers have found that strains made resistant to proguanil have retained their sensitivity to sulphadiazine, and Bishop (1951) was unable to confirm the earlier result. This cross-resistance is not dependent upon the pyrimidine part of the molecule, for Bishop and McConnachie (1950a) showed that a strain of P. gallinaceum resistant to sulphanilamide was also highly resistant to proguanil.…”

“…Resistance to sulphonamides could be attributed to a by-pass of the whole series of reactions from PAB to folinic acid, thereby render-I 4 212 ing the parasite insensitive not only to drugs interfering with reaction A but also to drugs interfering at B. Such a by-pass is, however, unlikely because Bishop and McConnachie (1950b) showed that strains treated with sulphadiazine readily became resistant to high doses of proguanil before any sign of sulphonamide resistance became evident. Hitchings (personal communication) has suggested that, in this instance, treatment with sulphadiazine may have resulted in an increase of the efficiency of reaction B.…”

Drug Resistance in Protozoa

“…The normal sensitivity of this strain to arsenical compounds had previously been (established by frequent tests though the strain itself had not been in contact with any drug. Paine & Finland, 1948;Miller & Bohnhoff, 1950;Mayr-Harting, 1955), and Bishop & McConnachie (19506) found that the growth of a sulphadiazine-resistant strain of P. gallinaceum, both in drug-treated and in untreated birds, was slower than that of the parent strain in untreated birds. Few observations have been made upon the growth of mixtures of drug-resistant and normal trypanosomes, but a salvarsan-resistant strain of T .…”

“…In some bacteria the growth rate of drug-resistant strains has been found to be lower than that of the normal parent strain (e.g. Paine & Finland, 1948;Miller & Bohnhoff, 1950;Mayr-Harting, 1955), and Bishop & McConnachie (19506) found that the growth of a sulphadiazine-resistant strain of P. gallinaceum, both in drug-treated and in untreated birds, was slower than that of the parent strain in untreated birds. It is possible, however, that not all resistant strains are at a selective disadvantage as compared with the normal strains.…”