Analysis Of The Finals Steps Of Megalomicin Biosynthesis: Generation Of New Megalomicin Analogues

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

San Miguel de Tucuman

Congreso; XLV Reunión Anual de la Sociedad Argentina de Investigadores en Bioquímica y Biología Molecular (SAIB); 2009

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

Megalomicins consist of a 14-membered macrolide which have shown antibacterial, antiparasitic and antiviral activities. The biosynthesis of megalomicin A was proposed to be similar to erithromycin D biosynthesis were the finals steps include hydroxylation of erithromycin D catalyzed by Meg K to generate erithromycin C and incorporation of a third sugar, megosamine, by a glycosyltransferase in order to generate megalomicin A. However this pathway was never validated In this work we have demonstrated that MegDI/MegDVI, the sugar transferases, catalyze the transfer of L-megosamine to either erythromycin C or erythromycin D, establishing two possible routes for the production of megalomicin A.  Flexibility of these enzymes towards the macrolide substrate allowed producing two new C-6-megosaminyl containing macrolides. The antibacterial activity of these new macrolides were tested on gram positive, gram negative bacteria  and gram positive bacteria resistant to macrolides, we observed that these compounds have less potency compare to the original molecules. On the other hand, we have evaluated the activity of these new compounds against P falsiparum. Preliminary dates showed that the new compounds are active against P.falsiparum resistant to macrolides which suggest a different mechanism of action of the new compounds in comparison to the original macrolides.