title: Apicoplast-targeting antibacterials inhibit the growth of Babesia parasites.
abstract: The apicoplast housekeeping machinery, specifically apicoplast DNA replication, transcription, and translation, was targeted by ciprofloxacin, thiostrepton, and rifampin, respectively, in the in vitro cultures of four Babesia species. Furthermore, the in vivo effect of thiostrepton on the growth cycle of Babesia microti in BALB/c mice was evaluated. The drugs caused significant inhibition of growth from an initial parasitemia of 1% for Babesia bovis, with 50% inhibitory concentrations (IC(50)s) of 8.3, 11.5, 12, and 126.6 μM for ciprofloxacin, thiostrepton, rifampin, and clindamycin, respectively. The IC(50)s for the inhibition of Babesia bigemina growth were 15.8 μM for ciprofloxacin, 8.2 μM for thiostrepton, 8.3 μM for rifampin, and 206 μM for clindamycin. The IC(50)s for Babesia caballi were 2.7 μM for ciprofloxacin, 2.7 μM for thiostrepton, 4.7 μM for rifampin, and 4.7 μM for clindamycin. The IC(50)s for the inhibition of Babesia equi growth 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% for Babesia bovis or Babesia bigemina, respectively. The three inhibitors caused immediate death of Babesia bovis and Babesia 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 of Babesia microti growth in BALB/c mice. These results implicate the apicoplast as a potential chemotherapeutic target for babesiosis.
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-Cho, Obihiro, Hokkaido, Japan.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Aboulaila
authors.forename: Tserendorj
authors.initials: T
authors.lastname: Munkhjargal
authors.forename: Thillaiampalam
authors.initials: T
authors.lastname: Sivakumar
authors.forename: Akio
authors.initials: A
authors.lastname: Ueno
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakano
authors.forename: Miki
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshinari
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagano
authors.forename: Koji
authors.initials: K
authors.lastname: Katayama
authors.forename: Nasr
authors.initials: N
authors.lastname: El-Bahy
authors.forename: Naoaki
authors.initials: N
authors.lastname: Yokoyama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001403:Babesia / Q000187:drug effects* / Q000235:genetics; D001404:Babesiosis; D015153:Blotting, Western; D002981:Clindamycin / Q000494:pharmacology; D005260:Female; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology; D013883:Thiostrepton / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D002981:Clindamycin; D013883:Thiostrepton; D012293:Rifampin