Production of ‘hybrid’ antibiotics by genetic engineering

Abstract

The recent development of molecular cloning systems in Streptomyces has made possible the isolation of biosynthetic genes for some of the many antibiotics produced by members of this important genus of bacteria. Such clones can now be used to test the idea that novel antibiotics could arise through the transfer of biosynthetic genes between streptomycetes producing different antibiotics. The likelihood of a 'hybrid' compound being produced must depend on the substrate specificities of the biosynthetic enzymes, about which little is known. In attempts to demonstrate hybrid antibiotic production, we therefore began with strains producing different members of the same chemical class of compounds in order to maximize the chance of success. Here we report the production of novel compounds by gene transfer between strains producing the isochromanequinone antibiotics actinorhodin, granaticin and medermycin. These experiments were made possible by the recent cloning of the whole set of genes for the biosynthetic pathway of actinorhodin from Streptomyces coelicolor A3(2) (ref. 8). We believe that this represents the first report of the production of hybrid antibiotics by genetic engineering.

Cloning, sequencing and heterologous expression of the medermycin biosynthetic gene cluster of Streptomyces sp. AM-7161: towards comparative analysis of the benzoisochromanequinone gene clusters

“…Its structure was shown (Tatsuta et al, 1990) to be identical with lactoquinomycin A, independently characterized as an anticancer compound from Streptomyces tanashiensis Okabe et al, 1985). Medermycin featured in the first production of hybrid antibiotics by genetic engineering (Hopwood et al, 1985), where a medermycin producer, Streptomyces sp. AM-7161, was transformed to produce mederhodins A and B (Ō mura et al, 1986).…”

Crystal Structure of Aclacinomycin Methylesterase with Bound Product Analogues

“…Because of their complex composition and structure, these compounds are difficult to synthesize chemically. The search for novel derivatives with less toxic side effects has therefore been limited so far to the hybrid antibiotic approach that rests on gene transfer of a particular set of genes from one Streptomyces species to another, resulting in production of novel anthracycline metabolites (5)(6). Alternative routes to non-natural anthracyclines could be based on knowledge of the three-dimensional structures of the enzymes involved in the biosynthesis of these metabolites.…”

Enzymology of FK‐506 biosynthesis

“…Due to the clinical and agricultural importance of some of the isolated compounds such as erythromycin [2], tylosin [3], avermectin [4] and others [5], extensive screening programs are currently underway in numerous laboratories searching for compounds having novel structures with useful pharmacological activities. In the mean time, extensive biochemical and genetic studies are being pursued in order to unravel the biosynthetic pathways for the formation of these complex structures, hoping, through gene manipulations [6], to improve the yield [7], biosynthesize modified [8] and hybrid [9] structures andor develop mutants [lo]. To these ends, a program was initiated in our laboratories to carry out biochemical and genetic studies on a newly discovered immunosuppressant agent, FK-506.…”