Apicoplast-Targeting Antibacterials Inhibit the Growth of Babesia Parasites

Abstract

ABSTRACTThe apicoplast housekeeping machinery, specifically apicoplast DNA replication, transcription, and translation, was targeted by ciprofloxacin, thiostrepton, and rifampin, respectively, in thein vitrocultures of fourBabesiaspecies. Furthermore, thein vivoeffect of thiostrepton on the growth cycle ofBabesia microtiin BALB/c mice was evaluated. The drugs caused significant inhibition of growth from an initial parasitemia of 1% forBabesia bovis, with 50% inhibitory concentrations (IC50s) of 8.3, 11.5, 12, and 126.6 μM for ciprofloxacin, thiostrepton, rifampin, and clindamycin, respectively. The IC50s for the inhibition ofBabesia bigeminagrowth were 15.8 μM for ciprofloxacin, 8.2 μM for thiostrepton, 8.3 μM for rifampin, and 206 μM for clindamycin. The IC50s forBabesia caballiwere 2.7 μM for ciprofloxacin, 2.7 μM for thiostrepton, 4.7 μM for rifampin, and 4.7 μM for clindamycin. The IC50s for the inhibition ofBabesia equigrowth were 2.5 μM for ciprofloxacin, 6.4 μM for thiostrepton, 4.1 μM for rifampin, and 27.2 μM for clindamycin. Furthermore, an inhibitory effect was revealed for cultures with an initial parasitemia of either 10 or 7% forBabesia bovisorBabesia bigemina, respectively. The three inhibitors caused immediate death ofBabesia bovisandBabesia equi. The inhibitory effects of ciprofloxacin, thiostrepton, and rifampin were confirmed by reverse transcription-PCR. Thiostrepton at a dose of 500 mg/kg of body weight resulted in 77.5% inhibition ofBabesia microtigrowth in BALB/c mice. These results implicate the apicoplast as a potential chemotherapeutic target for babesiosis.