Biosynthesis of the anti-parasitic agent megalomicin: transformation of erythromycin to megalomicin in Saccharopolyspora erythraea

Megalomicin is a therapeutically diverse compound which possesses antiparas itic, antiviral and antibacterial properties. It is produced by Micromonosp ora megalomicea and differs from the well-known macrolide antibiotic erythr omycin by the addition of a unique deoxyamino sugar, megosamine, to the C-6 hydroxyl. We have cloned and sequenced a 48 kb segment of the megalomicin (meg) biosynthetic gene cluster which contains the modular polyketide synth ase (PKS) and the complete pathway for megosamine biosynthesis. The similar ities and distinctions between the related megalomicin and erythromycin gen e clusters are discussed. Heterologous expression of the megalomicin PKS in Streptomyces lividans led to production of 6-deoxyerythronolide B, the sam e macrolactone intermediate for erythromycin. A 12 kb fragment harbouring t he putative megosamine pathway was expressed in Saccharopolyspora erythraea , resulting in the conversion of erythromycin to megalomicin. Considering t he extensive knowledge surrounding the genetic engineering of the erythromy cin PKS and the familiarity with genetic manipulation and fermentation of S . erythraea, the ability to produce megalomicin in this strain should allow the engineering of novel megalomicin analogues with potentially improved t herapeutic activities.