RESISTANCE TO THE ARSENICALS 757 



RESISTANCE TO THE ARSENICALS 



That certain organisms have the ability to develop a high degree of toler- 

 ance during exposure to the arsenicals has been recognized for over 50 

 years, inasmuch as the earliest work on the trypanocidal action of atoxyl 

 in Ehrlich's laboratory (Franke and Rohl, 1907) demonstrated recurrences 

 in infected animals in which the drug had lost its effectiveness. Resistance* 

 was first obtained experimentally by Browning (1907), on leave from 

 Glasgow and working in Frankfurt, who found that definite tolerance can 

 be developed within 10 days in infected mice and that this resistance is 

 maintained, in one case after 140 passages through mice over 14 months. 

 Ehrlich (1909) pointed out the specificity of resistance - — that trypano- 

 somes resistant to one arsenical may not be resistant to others, or that 

 organisms resistant-to other compounds, such as dyes, are not necessarily 

 resistant to the arsenicals — and explained this on the basis of his arseno- 

 receptor theory. In this connection it is worth pointing out, as did Yorke 

 and Murgatroyd (1930), that the term "arsenical resistance" is a misnomer 

 inasmuch as a nonspecific general tolerance to all arsenicals does not seem 

 to develop, but only resistance to certain classes of arsenicals. It also has 

 long been known that certain microorganisms possess a natural resistance; 

 fungi such as Cladosporium., Rhizopus, and Aspergillus can grow in Fowler's 

 solution, which is approximately 50 mM arsenite, unless other preservatives 

 are added. The growth of bacteria in arsenical cattle-dipping fluid was 

 first reported from Queensland in 1909 but the bacteria were not isolated 

 until 1918, and only recently has a study of this been made (Turner, 1954), 

 showing that species of Pseudomonas, Xanilwmonas , and Achromobacter 

 can grow in 20 40 niM arsenite and furthermore oxidize the arsenite, 

 although it is unknown whether they can derive energy from this process. 

 Resistance to the arsenicals is not only of practical interest but is a phenom- 

 enon which may possiblj^ shed some light on the mechanisms of arsenical 

 action since, as is the case with any drug tolerance, a study of the changes 

 occurring in these organisms may relate directly to the vulnerable systems 

 in the normal organisms. 



Resistance to the arsenicals has been demonstrated in a variety of bac- 

 teria, fungi, and protozoa. Some organisms, or strains, are apparently 

 naturally resistant and others achieve tolerance upon exposure to the arsen- 

 icals. Aside from the trypanosomes, upon which the most thorough work 

 has been done, acquired resistance has been demonstrated in spirochaetes 

 {Treponema and Borrelia), bacteria {Escherichia and Salmonella), infusoria 

 {Paramecium and Colpidium), and the South African blue tick {Boophilus). 



* In this section we shall be discussing acquired tolerance or resistance unless it 

 is otherwise specified. 



