title: Mycophenolic acid, mycophenolate mofetil, mizoribine, ribavirin, and 7-nitroindole inhibit propagation of Babesia parasites by targeting inosine 5'-monophosphate dehydrogenase.
abstract: The resistance of Babesia parasites to current anti-babesiosis drugs is an issue of major concern. The inosine 5'-monophosphate dehydrogenase (IMPDH) of Babesia gibsoni has been identified and characterized as a molecular drug target in our previous studies. In the present study, inhibitory effects of IMPDH inhibitors (mycophenolate mofetil, mizoribine, ribavirin, 7-nitroindole, and mycophenolic acid) were evaluated in vitro or in vivo. In the inhibition assay of recombinant B. gibsoni IMPDH activity, mycophenolate mofetil was the most potent inhibitor (IC(50) = 2.58 ± 1.32 μM) while ribavirin was the least potent. The inhibitory effects of mycophenolate mofetil, mizoribine, ribavirin, and 7-nitroindole on the in vitro growths of B. gibsoni and Babesia bovis were also assessed. The results revealed that mycophenolate mofetil was the most potent inhibitor of the multiplications of both B. gibsoni (IC(50) = 0.13 ± 0.05 μM) and B. bovis (IC(50) = 0.97 ± 0.49 μM). Ribavirin was also the least potent for both B. gibsoni and B. bovis in vitro. Mycophenolic acid, a metabolite of mycophenolate mofetil, caused an inhibition of Babesia microti in mice with noticeable improvement in hematological parameters of the infected mice (ED(50) = 44.15 ± 12.53 mg/kg). Although the report provides a non-exhaustive view of potential treatment strategy without addressing the potential adverse effect of immune suppression on infections, these results indicated that the IMPDH might be a molecular target of MPA for B. microti . Altogether, we provide a basis for development of antibabesia prodrugs by targeting IMPDH of the parasites in the treatment of babesiosis.
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan;
authors.forename: Shinuo
authors.initials: S
authors.lastname: Cao
authors.forename: Gabriel Oluga
authors.initials: GO
authors.lastname: Aboge
authors.forename: Mohamad Alaa
authors.initials: MA
authors.lastname: Terkawi
authors.forename: Mo
authors.initials: M
authors.lastname: Zhou
authors.forename: Ketsarin
authors.initials: K
authors.lastname: Kamyingkird
authors.forename: Paul Franck Adjou
authors.initials: PF
authors.lastname: Moumouni
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Masatani
authors.forename: Ikuo
authors.initials: I
authors.lastname: Igarashi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Xuenan
authors.initials: X
authors.lastname: Xuan
mesh_terms: D000818:Animals; D001403:Babesia / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D020128:Inhibitory Concentration 50; D051379:Mice; D008813:Mice, Inbred ICR; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D012254:Ribavirin / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D012263:Ribonucleosides; D012254:Ribavirin; C010052:mizoribine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid