Abstract
Boromycin is a boron-containing macrolide antibiotic produced by Streptomyces antibioticus with potent activity against certain viruses, Gram-positive bacteria and protozoan parasites. Most antimalarial antibiotics affect plasmodial organelles of prokaryotic origin and have a relatively slow onset of action. They are used for malaria prophylaxis and for the treatment of malaria when combined to a fast-acting drug. Despite the success of artemisinin combination therapies, the current gold standard treatment, new alternatives are constantly needed due to the ability of malaria parasites to become resistant to almost all drugs that are in heavy clinical use. In vitro antiplasmodial activity screens of tetracyclines (omadacycline, sarecycline, methacycline, demeclocycline, lymecycline, meclocycline), macrolides (oleandomycin, boromycin, josamycin, troleandomycin), and control drugs (chloroquine, clindamycin, doxycycline, minocycline, eravacycline) revealed boromycin as highly potent against Plasmodium falciparum and the zoonotic Plasmodium knowlesi. In contrast to tetracyclines, boromycin rapidly killed asexual stages of both Plasmodium species already at low concentrations (~ 1 nM) including multidrug resistant P. falciparum strains (Dd2, K1, 7G8). In addition, boromycin was active against P. falciparum stage V gametocytes at a low nanomolar range (IC50: 8.5 ± 3.6 nM). Assessment of the mode of action excluded the apicoplast as the main target. Although there was an ionophoric activity on potassium channels, the effect was too low to explain the drug´s antiplasmodial activity. Boromycin is a promising antimalarial candidate with activity against multiple life cycle stages of the parasite.
Highlights
Malaria remains one of the world’s most serious public health problems, especially in tropical and subtropical areas, with approximately 241 million cases and 627,000 deaths in 2020 (World Health Organization, 2021)
P. falciparum was exposed to 15 antibiotics and chloroquine for 3 and for 6 days
None of the tetracyclines evaluated in this study showed a pronounced activity in the 3-day assay against P. falciparum, but had some delayed activity after 6 days of drug exposure (Table 1)
Summary
Malaria remains one of the world’s most serious public health problems, especially in tropical and subtropical areas, with approximately 241 million cases and 627,000 deaths in 2020 (World Health Organization, 2021). Intracellular parasites of the genus Plasmodium cause the disease, and among the six species that can infect humans P. falciparum, P. vivax, P. malariae, P. ovale wallikeri, P. ovale curtisi, and the zoonotic species P. knowlesi (Rutledge et al, 2017; Grignard et al, 2019), P. falciparum is the most virulent (World Health Organization, 2021). Clinical symptoms of malaria appear during the replication of parasites in the erythrocytic cycle (lasting approximately 24 h for P. knowlesi and 48 h for P. falciparum) in the human host (van Biljon et al, 2018). These symptoms can develop into life-threatening complications such as severe anemia, liver and kidney failure and cerebral malaria if not treated properly (Milner et al, 2014). Gametocytes are non-dividing parasite stages with low metabolic activity whose immature stages are hidden in the bone marrow while the mature stage (stage V) circulates in the blood stream (Gardiner and Trenholme, 2015)
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