Production of new erythromicin derivatives with antimalaria properties

GRAMAJO HUGO

Workshop; Workshop in Natural Products to combat diseases in the developing world; 2016

We have synthesized new derivatives of the macrolide antibiotics erythromycin and azithromycin. Novel deoxysugar moietieswere attached to these standard antibiotics by biotransformation using a heterologous host. The resulting compounds weretested against several standard laboratory and clinically isolated bacterial strains. In addition, they were also tested in vitroagainst standard and drug-resistant strains of human malaria parasites (Plasmodium falciparum) and the liver stages of the rodentmalaria parasite (Plasmodium berghei). Antibacterial activity of modified erythromycin and azithromycin showed no improvementover the unmodified macrolides, but the modified compounds showed a 10-fold increase in effectiveness after ashort-term exposure against blood stages of malaria. The new compounds also remained active against azithromycin-resistantstrains of P. falciparum and inhibited growth of liver-stage parasites at concentrations similar to those used for primaquine.Our findings show that malaria parasites have two distinct responses to macrolide antibiotics, one reflecting the prokaryotic originof the apicoplast and a second, as-yet uncharacterized response that we attribute to the eukaryotic nature of the parasite.This is the first report for macrolides that target two different functions in the Plasmodium parasites.