Insights into the preclinical treatment of blood‐stage malaria by the antibiotic borrelidin

• Published in: British journal of pharmacology Vol. 169; no. 3; pp. 645 - 658
• Main Authors: Azcárate, IG, Marín‐García, P, Camacho, N, Pérez‐Benavente, S, Puyet, A, Diez, A, Ribas de Pouplana, L, Bautista, JM
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2013
• Subjects: aminoacyl‐tRNA synthetases; Animals; Antibodies, Protozoan - analysis; Antibodies, Protozoan - metabolism; Antibody Affinity - drug effects; Antimalarials - pharmacology; Antimalarials - therapeutic use; borrelidin; Drug Evaluation, Preclinical; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Fatty Alcohols - pharmacology; Fatty Alcohols - therapeutic use; Female; humoral response; Immunity, Humoral - drug effects; malaria; Malaria - drug therapy; Malaria - immunology; Malaria - parasitology; Malaria - prevention & control; Mice; Mice, Inbred Strains; Mupirocin - therapeutic use; Parasitemia - drug therapy; Parasitemia - immunology; Parasitemia - parasitology; Parasitemia - prevention & control; Plasmodium; Plasmodium yoelii - drug effects; Plasmodium yoelii - immunology; Plasmodium yoelii - isolation & purification; Plasmodium yoelii - physiology; Protozoan Proteins - blood; Protozoan Proteins - isolation & purification; Protozoan Proteins - metabolism; Random Allocation; Research Papers; Schizonts - drug effects; Schizonts - immunology; Schizonts - metabolism; Schizonts - physiology; Secondary Prevention; Specific Pathogen-Free Organisms; Survival Analysis; Threonine-tRNA Ligase - antagonists & inhibitors; treatment
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12156

Background and Purpose Blood‐stage Plasmodium parasites cause morbidity and mortality from malaria. Parasite resistance to drugs makes development of new chemotherapies an urgency. Aminoacyl‐tRNA synthetases have been validated as antimalarial drug targets. We explored long‐term effects of borrelidin and mupirocin in lethal P. yoelii murine malaria. Experimental Approach Long‐term (up to 340 days) immunological responses to borrelidin or mupirocin were measured after an initial 4 day suppressive test. Prophylaxis and cure were evaluated and the inhibitory effect on the parasites analysed. Key Results Borrelidin protected against lethal malaria at 0.25 mg·kg−1·day−1. Antimalarial activity of borrelidin correlated with accumulation of trophozoites in peripheral blood. All infected mice treated with borrelidin survived and subsequently developed immunity protecting them from re‐infection on further challenges, 75 and 340 days after the initial infection. This long‐term immunity in borrelidin‐treated mice resulted in negligible parasitaemia after re‐infections and marked increases in total serum levels of antiparasite IgGs with augmented avidity. Long‐term memory IgGs mainly reacted against high and low molecular weight parasite antigens. Immunofluorescence microscopy showed that circulating IgGs bound predominantly to late intracellular stage parasites, mainly schizonts. Conclusions and Implications Low borrelidin doses protected mice from lethal malaria infections and induced protective immune responses after treatment. Development of combination therapies with borrelidin and selective modifications of the borrelidin molecule to specifically inhibit plasmodial threonyl tRNA synthetase should improve therapeutic strategies for malaria.