Mutagenic activation of CL64,855, an anti-Trypanosoma cruzi nitroderivant, by bacterial nitroreductases

Abstract

CL64,855 is a nitroimidazole-thiodiazole derivate with high anti-Trypanosoma cruzi activity. CL64,855-induced mutagenesis in the Salmonella/microsome test was detected by TA98 and TA98dnp6 strains, but not by the nitroreductase I-deficient TA98nr strain. The lack of mutagenic response of TA98nr was connected with its extreme resistance to the killing effect of the drug. Presence of S9 mix did not restore mutagenic activity of CL64,855 to the TA98nr strain. Additionally, CL64,855 was reduced in vitro by the nitroreductase I-proficient TA98 strain, mainly in the presence of oxygen, but not by the TA98nr strain. Mutagenic activity was detected in serum samples of treated guinea pigs by nitroreductase-proficient strains TA98 and TA98dnp6, but not by nitroductase-deficient strain TA98nr. In the case of urine, mutagenic activity was observed with all three tested strains, suggesting an in vivo metabolic activation of the drug by a distinct metabolic pathway.