Involvement of Mitochondrial Genes of <i>Babesia gibsoni</i> in Resistance to Diminazene Aceturate

Abstract

aBsTracT. The stability of the characteristics of the diminazene aceturate (Da)-resistant B. gibsoni isolate was initially determined in vitro. Part of the Da-resistant B. gibsoni isolate was cultured without Da for 4 weeks, and then newly exposed to 200 ng/ml Da. as a result, this isolate could proliferate the same as the Da-resistant isolate, indicating that the characteristic of Da resistance was stable in the Daresistant isolate. additionally, the level of parasitemia in the Da-resistant isolate was comparatively lower than in the wild-type, suggesting that the proliferation potential of the Da-resistant isolate would be lower than that of the wild-type. subsequently, to investigate the involvement of mitochondrial DNa (mtDNa) in Da resistance in B. gibsoni, the nucleotide sequences and deduced amino acid sequences of mitochondrial genes such as COXI, COXIII, and CYTb genes of the Da-resistant isolate, were compared with those of the wild-type. as a result, these three genes were not altered in the Da-resistant B. gibsoni isolate. moreover, the transcription levels of COXI, COXIII, and CYTb genes were observed by semi-quantitative rT-Pcr. as a result, the gene transcription of those genes in the Da-resistant isolate was not significantly altered. These results indicated that DA did not affect mtDNA directly in DA-resistant B. gibsoni. Thus, it is suggested that mtDNa should not be deeply involved in Da resistance in B. gibsoni. Babesia gibsoni is a blood protozoan of dogs and a causative pathogen of canine babesiosis [34]. It is difficult to eliminate this parasite from infected dogs, although a number of drugs, including diminazene aceturate (Da), clindamycin, metronidazole, pentamidine, and atovaquone combined with azithromycin, are used for treatment of the disease [9,16,22,29]. in the treatment of canine babesiosis, possible relapses and the development of drug-resistant isolates are matters of concern.Da, an aromatic diamidine derivative, has been used as a first-line agent for the treatment of B. gibsoni infection in dogs [22]; however, Da cannot eliminate B. gibsoni from infected dogs, and relapses often occur [5,8,17,29]. in addition, a Da-resistant B. gibsoni isolate was previously developed in vitro in our laboratory [8]. However, the mechanism of action of Da on B. gibsoni has not been elucidated, and the mechanism of the development of Da resistance in B. gibsoni is still not known. To treat canine babesiosis with Da effectively, these problems have to be clarified. The DA-resistant B. gibsoni isolate developed by Hwang et al. was more resistant to pentamidine, clindamycin and doxycycline than the wild-type [8]. Furthermore, the transcription levels of the heat shock protein 70 (hsp70) gene in this isolate decreased during the development of the Da-resistant isolate, suggesting that the hsp70 gene is involved but does not play a major role in the development of the Da-resistant isolate. Thus, we have very little knowledge of the mechanism of the Da resistance of B. gibsoni. in Trypanosoma and Lei...

Chemotherapeutic efficacies of a clofazimine and diminazene aceturate combination against piroplasm parasites and their AT-rich DNA-binding activity on Babesia bovis

“…The currently available anti-piroplasm drugs, diminazene aceturate (DA) and imidocarb dipropionate, have sometimes been reported to have toxic side effects 3 . In addition, DA-resistant Babesia gibsoni and the development of imidocarb dipropionate–resistant Theileria equi have been reported 4 , 5 . Therefore, less-toxic, low-cost and potent anti-piroplasm chemotherapies are urgently needed.…”

The epidemiological survey for atovaquone resistant related gene of <i>Babesia gibsoni</i> in Japan

“…Although the mechanisms for this change and the pharmacokinetics have not yet been unraveled, other factors in dog might affect the changing M121I population. It is also reported that three amino acid substitutions on cyt b related to ATV resistance were detected in a clinical case in Hyogo Prefecture [ 12 ]. These substitutions included M121I, and this dog received ATV treatment.…”

Therapeutic Effects of Atranorin towards the Proliferation of Babesia and Theileria Parasites

“…Currently, chemotherapy treatments against piroplasmosis remain inadequate. Oxytetracycline, imidocarb dipropionate and diminazene aceturate (DA) are considered the main choices for the Pathogens 2020, 9, 127 2 of 14 treatment of piroplasm parasites that infect cattle and horses, although there have been cases of toxic effects related to these drugs [1,2], as well as the development of imidocarb dipropionate-resistant Theileria equi and DA-resistant Babesia gibsoni [3,4]. Combined atovaquone (AV) and azithromycin therapy is still the best choice against human zoonotic babesiosis due to its low side effects [5].…”

“…Pathogens 2020, 9, x FOR PEER REVIEW 2 of 14 effects related to these drugs [1,2], as well as the development of imidocarb dipropionate-resistant Theileria equi and DA-resistant Babesia gibsoni [3,4]. Combined atovaquone (AV) and azithromycin therapy is still the best choice against human zoonotic babesiosis due to its low side effects [5].…”