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

Amany Magdy Beshbishy,Eman Nadwa,Luay Alkazmi,Gaber El-Saber Batiha,Eman Rashwan,Ikuo Igarashi,Ahmed Abdeen,Naoaki Yokoyama

doi:10.3390/pathogens9020127

Abstract

Atranorin (ATR), is a compound with multidirectional biological activity under different in vitro and in vivo conditions and it is effective as an antibacterial, antiviral, antiprotozoal and anti-inflammatory agent. In the current study, the in vitro as well as in vivo chemotherapeutic effect of ATR as well as its combined efficacy with the existing antibabesial drugs (diminazene aceturate (DA), atovaquone (AV) and clofazimine (CF)) were investigated on six species of piroplasm parasites. ATR suppressed B. bovis, B. bigemina, B. divergens, B. caballi and T. equi multiplication in vitro with IC50 values of 98.4 ± 4.2, 64.5 ± 3.9, 45.2 ± 5.9, 46.6 ± 2.5, and 71.3 ± 2.7 µM, respectively. The CCK test was used to examine ATR’s cytotoxicity and adverse effects on different animal and human cell lines, the main hosts of piroplasm parasites and it showed that ATR affected human foreskin fibroblasts (HFF), mouse embryonic fibroblast (NIH/3T3) and Madin-Darby Bovine Kidney (MDBK) cell viability in a dose-related effect with a moderate selective index. The combined efficacy of ATR with DA, CF, and AV exhibited a synergistic and additive efficacy toward all tested species. In the in vivo experiment, ATR prohibited B. microti multiplication in mice by 68.17%. The ATR-DA and ATR-AV combination chemotherapies were more potent than ATR monotherapy. These results indicate the prospects of ATR as a drug candidate for piroplasmosis treatment.

Highlights

50 values obtained from ATR was lower than that showed by N-acetyl-L-cysteine [18], Allicin [19], thymoquinone against equine piroplasms parasites [20], norfloxacin, ofloxacin [21], trans-chalcone and thymoquinone piroplasms parasites [20], norfloxacin, ofloxacin trans-chalcone chalcone hydrateagainst againstequine
T. equi treated with ATR relapsed even at 6 × IC50 concentration. These results revealed the effectiveness of ATR toward Babesia parasites rather than Theileria parasites
The in vitro inhibitory effects of ATR motivated us to assess their chemotherapeutical prospects on B. microti infection in mice, and we found that it was effective in this context as well

Summary

Introduction

Chemotherapy treatments against piroplasmosis remain inadequate. Oxytetracycline, imidocarb dipropionate and diminazene aceturate (DA) are considered the main choices for the Pathogens 2020, 9, 127; doi:10.3390/pathogens9020127 www.mdpi.com/journal/pathogensPathogens 2020, 9, x FOR PEER REVIEW treatment of piroplasm parasites that infect cattle and horses, there have been cases of toxic effects related to these these drugs drugs [1,2],[1,2], as as well well as as the the development development of of imidocarb imidocarb dipropionate–resistant dipropionate–resistantTheileria equi and atovaquone (AV) and azithromycin and DA-resistantDA-resistant BabesiaBabesia gibsoni gibsoni [3,4].[3,4]. Pathogens 2020, 9, x FOR PEER REVIEW treatment of piroplasm parasites that infect cattle and horses, there have been cases of toxic effects related to these these drugs drugs [1,2],. Theileria equi and atovaquone (AV) and azithromycin and DA-resistant. Combined atovaquone azithromycin therapy against human zoonotic babesiosis duedue to itstolow [5]. Order therapy isisstill stillthe thebest bestchoice choice against human zoonotic babesiosis its side low effects side effects. In to address the shortcomings in the therapeutic options available for these parasitic diseases, new drugs order to address the shortcomings in the therapeutic options available for these parasitic diseases, are [2].required [2].

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Conclusion