An investigation of the biosynthesis of carbapenem-beta-lactams by Streptomyces cattleya.

This thesis is divided into five chapters. Chapter one provides a brief outline of the history of beta-lactams. New developments in screening methodology and current understanding of the mode of action of beta-lactams are presented. A section on the biosynthesis of beta-lactams is included. Our aim in this project was to develop a system for investigation of the biosynthetic pathway leading to Thienamycin, the first representative of a unique class of beta-lactams - the carbapenems. It was recognised that due to the intrinsic instability of Thienamycin and non availability of a high yielding strain, that the essential preliminaries of development of a fermentation and convenient assay techniques would form a major part of the effort. Chapter two describes the fermentation studies carried out with Streptomyces cattleya and includes brief coverage of regulatory controls that may influence antibiotic production in Streptomyces. Possible causes of the significant degree of variability in B-lactam production, observed in S. cattleya fermentation are also presented. Chapter three covers the development of analytical techniques used in the detection and identification of Thienamycin and co-produced beta-lactams. An attempt was made to discriminate between co-produced carbapenems on the basis of their structure-activity relationship. The major beta-lactam product of fermentation was identified as Thienamycin. The experimental section is to be found in chapter four. Chapter five reviews the results of our studies with S. cattleya, the main emphasis of the work being directed to optimising the fermentation and assay systems. Current understanding of the biosynthesis of carbapenems in Streptomyces sp. with particular attention to production of Thienamycin by S. cattleya, together with recent developments in the field of biosynthesis, such as protoplast and genetic engineering techniques are also discussed