THE SPONTANEOUS DEVELOPMENT OF ARSENIC-RESISTANCE IN TRYPANOSOMA EQUIPERDUM, AND ITS MECHANISM

¹ From the U. S. Public Health Service Venereal Disease Research and Postgraduate Training Center, Johns Hopkins Hospital, Baltimore 5, Maryland

1. There is reported the spontaneous development of a strain of T. equiperdum resistant to amino- and amide-substituted phenyl arsenoxides and their derivatives. The circumstances surrounding the development of this strain suggest that the change did not occur as the result of selection, but as a spontaneous variation.

2. The organisms were 5 to 200 times more resistant to amino- and amide-substituted phenyl arsenoxides than was the parent strain, and the resistance was observed in vivo as well as in vitro. Their susceptibility to the unsubstituted phenyl arsenoxide, to derivatives with substituents which affect neither activity nor toxicity (e.g.—CH₃,—Cl), and to acid-substituted phenyl arsenoxides, was, however, unchanged.

3. The p-(CH₂)₃COOH phenyl arsenoxide, previously described as a compound with a favorable chemotherapeutic index in experimental trypanosomiasis, may be of particular therapeutic value because of its maintained activity against this, and perhaps other strains resistant to amino- and amide-substituted compounds.

4. The resistant organisms bound far less arsenic than the parent strain from solutions of the p-SO₂NH₂ or p-CONHCH₂CONH₂ phenyl arsenoxide, to which they were no longer susceptible; but their affinity for unsubstituted phenyl arsenoxide and its p-(CH₂)₃COOH or p-Cl derivatives, to which they were normally susceptible, remained unchanged.

5. In the above respects the organism resembled the strain of T. rhodesiense described by Yorke, Murgatroyd and Hawking, and rendered arsenic-resistant by repeated exposure to arsenicals.

6. Current theories as to the underlying mechanism of this selective arsenic-resistance are discussed. It is suggested that the primary factor which determines the activity of arsenicals, whether against normal or resistant trypanosomes, is the degree to which they are bound by the organisms, and that arsenic-resistant strains are modified in the sense that the cell membrane becomes less permeable to certain arsenicals. It is further suggested that, as in the present case, in many instances this change may not be induced by the arsenical, but may occur spontaneously either as a true genetic mutation, or as a temporary variation (Dauermodifikation-Jollos). Under these circumstances the suggested function of the arsenical is to make that mutation or variation apparent by acting as a selective factor fortuitously toxic to the parent, but not to the variant, strain.