The Mode of Action of Certain 3- and 5-Nitropyridines and Pyrimidines. IV. Development of Drug-Resistance by Trichomonas vaginalis.

SYNOPSIS. Certain 5-nitropyridines and pyrimidines are growth inhibitory to Trichomonas vaginalis in vitro. Populations were made resistant either to 2-amino-5-nitropyrimidine, or 2-amino-5-nitropyridine, or 2-hydroxy-5-nitropyridine, by growth in gradually increasing concentrations of one of these inhibitors. After resistance was maximal, clonal lines were established. The development of resistance to any one of these inhibitors was accompanied by resistance to the other two. Since cross-resistance was complete, these inhibitors act at the same locus. This in vitro resistance persisted in vivo.
Resistance was accompanied by an increase in the generation time and a decrease in the maximal obtainable population. These growth parameters were unique for each resistant clone. The growth of the clone made resistant to 2-amino-5-nitropyridine was the closest to the normal clone. Its metabolic capacity, as measured by conventional Warburg techniques, was less than half of the parent strain and anaerobically was the same as had been previously found for non-resistant cells which had been grown for 3 hr with inhibitor. The mechanisms of killing by the inhibitor and the development of drug resistance are the same. The inhibitor kills the cells by holding them in an early metabolic sequence. Some of them succeed in growing by using this metabolic sequence and reinforcing it with an alternate aerobic route.