Biosynthesis of the orthosomycin antibiotic avilamycin A: deductions from the molecular analysis of the avi biosynthetic gene cluster of Streptomycesviridochromogenes Tu57 and production of new antibiotics

Background: Streptomyces viridochromogenes Tu57 is the producer of avilamyc in A. The antibiotic consists of a heptasaccharide side chain and apolyketi de-derived dichloroisoeverninic acid as aglycone. Molecular cloning and cha racterization of the genes governing the avilamycin A biosynthesis is of ma jor interest as this information might set the direction for the developmen t of new antimicrobial agents. Results: A 60-kb section of the S. viridochromogenes Tu57 chromosome contai ning genes involved in avilamycin biosynthesis was sequenced. Analysis of t he DNA sequence revealed 54 open reading frames. Based on the putative func tion of the gene products a model for avilamycin biosynthesis is proposed. Inactivation of aviG4 and aviH, encoding a methyltransferase and a halogena se, respectively, prevented the mutant strains from producing the complete dichloroisoeverninic acid moiety resulting in the accumulation of new antib iotics named gavibamycins. Conclusions: The avilamycin A biosynthetic gene cluster represents an inter esting system to study the formation and attachment of unusual deoxysugars. Several enzymes putatively responsible for specific steps of this pathway could be assigned. Two genes encoding enzymes involved in post-PKS tailorin g reactions were deleted allowing the production of new analogues of avilam ycin A. (C) 2001 Elsevier Science Ltd. All rights reserved.