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Babesia bigemina  is a tick-borne apicomplexan hemoprotozoan responsible for bovine babesiosis. The current drugs used for bovine babesiosis treatment have several drawbacks, including toxicity, the lack of effectiveness to clear the parasite, and potential to develop resistance. Identifying compounds that target essential and unique parasite metabolic pathways is a rational approach toward finding alternative drug treatments. Based on the genome sequence and transcriptomics analysis, it can be inferred that anaerobic glycolysis is the dominant adenosine triphosphate (ATP) supply for  Babesia , and lactate dehydrogenase (LDH) is one of the essential enzymes in this pathway. Furthermore, the  Babesia  LDH sequence is distinct from its bovine homologue and thus a potential chemotherapeutic target that would result in decreasing the ATP supply to the parasite but not to the host. Gossypol is a known efficient specific inhibitor of LDH in the  sensu stricto B. bovis  and the  sensu lato B. microti , among other related parasites, but no such data are currently available in the  sensu stricto B. bigemina  parasites. Hereby, we show that the LDH amino acid sequence is highly conserved among  sensu stricto  but not in  sensu lato Babesia  spp. A predictive structural analysis of  B. bigemina  LDH showed the conservation of the key amino acids involved in the binding to gossypol compared to  B. bovis . Gossypol has a significant (P &amp;lt; 0.0001) inhibitory effect on the  in vitro  growth of  B. bigemina , with IC 50  of 43.97 mM after 72 h of treatment. The maximum IC (IC 98 ) was observed at 60 mM gossypol. However, a significant effect on the viability of cattle PBMC was observed when the cells were cultured with 60 mM (IC 98 ) gossypol compared with DMSO-exposed control cells. Interestingly,  B. bigemina  cultured at 3% oxygen expresses significantly higher levels of LDH and is more resistant to gossypol than the parasites maintained at ambient conditions containing ~20% oxygen. Altogether, the results suggest the potential of gossypol as an effective drug against  B. bigemina  infection, but the risk of host toxicity at therapeutic doses should be further evaluated in  in vivo  studies.

Lactate Dehydrogenase as a Potential Therapeutic Drug Target to Control Babesia bigemina