In vivo activity and atom pair fingerprint analysis of MMV665941 against the apicomplexan parasite Babesia microti, the causative agent of babesiosis in humans and rodents

ABSTRACT

The effect of MMV665941 on the growth of Babesia microti (B. microti) in mice, was investigated in this study using a fluorescence-based SYBR Green I test. Using atom Pair signatures, we investigated the structural similarity between MMV665941 and the commonly used antibabesial medicines diminazene aceturate (DA), imidocarb dipropionate (ID), or atovaquone (AV). In vitro cultures of Babesia bovis (B. bovis) and, Theileria equi (T. equi) were utilized to determine the MMV665941 and AV interaction using combination ratios ranged from 0.75 IC₅₀ MMV665941:0.75 IC₅₀ AV to 0.50 IC₅₀ MMV665941:0.50 IC₅₀ AV. The used combinations were prepared depending on the IC₅₀ of each drug against the in vitro growth of the tested parasite. Every 96 h, the hemolytic anemia in the treated mice was monitored using a Celltac MEK-6450 computerized hematology analyzer. A single dose of 5 mg/kg MMV665941 exhibited inhibition in the B. microti growth from day 4 post-inoculation (p.i.) till day 12 p.i. MMV665941 caused 62.10%, 49.88%, and 74.23% inhibitions in parasite growth at days 4, 6 and 8 p.i., respectively. Of note, 5 mg/kg MMV665941 resulted in quick recovery of hemolytic anemia caused by babesiosis. The atom pair fingerprint (APfp) analysis revealed that MMV665941 and atovaquone (AV) showed maximum structural similarity. Of note, high concentrations (0.75 IC₅₀) of MMV665941 and AV caused synergistic inhibition on B. bovis growth. These findings suggest that MMV665941 might be a promising drug for babesiosis treatment, particularly when combined with the commonly used antibabesial drug, AV.

KEYWORDS:

• Babesia microti
• MMV665941
• in vivo
• structural similarity measurements
• atovaquone

Acknowledgments

The authors would like to great thank Prof. Naoaki Yokoyama, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, Japan for his scientific support and discussion.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data and materials accessibility

On reasonable request, the corresponding authors will provide the datasets created and/or analyzed during the current work.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/20477724.2022.2128571

Additional information

Funding

This study was supported financially by the Medicines for Malaria Venture Malaria Box Challenge Grant. Mohamed Abdo Rizk is supported by a research grant fellowship for young scientists from the Japan Society for the Promotion of Science (JSPS) (ID no. P18091).