The Mechanism of Drug Resistance in Trypanosomes: II. A Method for the Differential Staining of Normal and Drug Resistant Trypanosomes and its Possible Relation to the Mechanics of Drug Resistance

Drug Resistance in Trypanosomes; Cross‐resistance Analyses

“…The resistance produced by stilbamidine apparently involves a more fundamental change in the drug " receptors " than is implied by the suggestion of Schueler (1947) of a shift in the isoelectric point of protein in resistant strains. If this mechanism operated in the stilbamidine-fast strain, the decrease in net negative charge of the receptor structure, as manifested by resistance to cationic drugs, should be accompanied by an increased net positive charge tending to produce an increased sensitivity to anionic trypanocides, instead of the resistance which is actually found.…”

“…We have attempted to extend the evidence for an ionic .basis of the trypanocidal action and resistance behaviour of acidic and basic drugs (King and Strangeways, 1942;Schueler, 1947) by using as wide a variety of anionic trypanocides as possible. Unfortunately, of the series of acid dyes tested, several of which had been reported as trypanocidal, only two, trypan blue and pontamine sky blue 5BX, were active against our parent T. rhodesiense strain.…”

“…One of the more plausible current theories of the resistance mechanism in trypanosomes (Schueler, 1947) implies that the ionic properties of a drug molecule control to a large extent the subsequent cross-resistance behaviour of a strain made resistant to it. For example, the strain made resistant to the atoxyl-tryparsamide-oxophenarsinetype of arsenical, in which the substituents are hydrophilic but ionize only feebly or not at all, is normally sensitive to trypanocides with ionizable substituents (anionic or cationic).…”

Drug Resistance in Trypanosomes; Selective Interference With Trypanocidal Action

“…The nature of the cellular "receptor " groups will be considered in a later report, but it is reasonable to assume that the trypanocides which are ionized at blood pH will combine with oppositely charged ionized groups in trypanosome cell material. This is the basis of the " isoelectric point shift" resistance theory of Schueler (1947) Alexander, 1952;Kopac, 1947).…”

“…There is no correlation with pKa (carboxyl); any shift in pKa value (carboxyl or amino group) is progressive as the series is ascended, and all four compounds are 99% ionized as anions at blood pH. Schueler (1947) has indicated that, by virtue of the n-butyric acid side-chain which could assume an incomplete hexagonal structure on the basis of the normal carbon bond angle, butarsen may exist in forms where there is a much reduced distance between the arsenoso and carboxyl groups. This distance is likely to be of the order of separation of the amino and carboxyl groups in p-aminobenzoic acid (6.7 A: Roblin and Bell, 1943), and this factor, combined with the similarity in acid strength of the two compounds, may be responsible for the specificity of the interference.…”