Chemobiosynthesis of new antimalric macrolides

USEGLIO, M; PEIRÚ, S; GOODMAN, D; RODRÍGUEZ, E; GRAMAJO, H

Potrero de Funes

Congreso; XLVII Reunión Anual de la Sociedad Argentina de Investigadores en Bioquímica y Biología Molecular (SAIB).; 2011

Previously we have synthesized macrolide derivatives meg-azi and meg-ery through biotransformation experiments using a heterologous host and demonstrated substrate flexibility of the sugar transferase for the macrolide substrate. Now new macrolide derivatives were synthesized by expression of alternative TDPaminosugar operons. These results demonstrate also substrate flexibility towards the TDP-aminosugar recognized by the sugar tranferases. Antibacterial and antiparasitic activities were determined for these derivatives. Antibacterial activity of these new derivatives did not change notably compared to original molecules. Meg-azi and meg-ery derivatives were tested in vitro against a standard laboratory and a mefloquine resistant strain of Plasmodium falciparum. These compounds showed a ten-fold increase in effectiveness after a short-term exposure and retained the similar effectiveness to azithromycin after longer exposures. The new compound also remains active against azithromycin resistant strains of P. falciparum. These results encourage us to synthesize new modified forms of these compounds to further improve the short term activity and evaluating the antibacterial and antiparasitic activity of these new compounds.