Final Activity Report Summary - BOPA (Characterisation and engineering of the biosynthetic pathways of two model pyrrole amide antibiotics, congocidine and distamycin)
Heart diseases, stroke, cancer, AIDS, chronic diseases such as arthritis and antibiotic resistance in pathogens are some of the major challenges facing medicine today. To win these important battles, medicine is relying critically on the discovery of new biologically active molecules. Natural products are an excellent source of bioactive compounds and for thousands of years, humans have relied on them for their remedies and medicines. Today, many drugs from our pharmacopoeia are still inspired or derived from natural products. This is especially true in the areas of antibacterial or anticancer drugs, where natural products or their derivatives represent between two thirds and three quarters of the new molecules showing promising biological activities.
Most of the natural products used in medicine are produced by plants or micro-organisms. Among micro-organisms, Streptomyces are particularly prolific natural products producers. This on-going project aims at understanding the biological and chemical mechanisms underlying the biosynthesis of pyrrole amides, a family of natural products produced by Streptomyces and related actinobacteria. Their ability to bind DNA confer them a variety of biological activities (antibacterial or antiviral for example). More specifically, this project focuses on two related pyrrole amides congocidine and distamycin. Ultimately, the knowledge gained from these studies will be used to engineer analogues of these molecules and generate new biologically active molecules.
The genes directing the biosynthesis of congocidine have been isolated and sequenced. The study of the role of each of the 24 genes identified has been undertaken. So far, four of these genes have been shown to be essential for congocidine biosynthesis and two are defence mechanisms that allow the bacterium not to be killed by congocidine, which is has an antibacterial activity (resistance genes). Information resulting from this study has already allowed us to propose a plausible biosynthetic pathway (chemical reactions involved in the synthesis of congocidine). Verification of this hypothetical pathway has been undertaken. Finally, genes directing the biosynthesis of distamycin have been isolated and their sequencing is under way.
Most of the natural products used in medicine are produced by plants or micro-organisms. Among micro-organisms, Streptomyces are particularly prolific natural products producers. This on-going project aims at understanding the biological and chemical mechanisms underlying the biosynthesis of pyrrole amides, a family of natural products produced by Streptomyces and related actinobacteria. Their ability to bind DNA confer them a variety of biological activities (antibacterial or antiviral for example). More specifically, this project focuses on two related pyrrole amides congocidine and distamycin. Ultimately, the knowledge gained from these studies will be used to engineer analogues of these molecules and generate new biologically active molecules.
The genes directing the biosynthesis of congocidine have been isolated and sequenced. The study of the role of each of the 24 genes identified has been undertaken. So far, four of these genes have been shown to be essential for congocidine biosynthesis and two are defence mechanisms that allow the bacterium not to be killed by congocidine, which is has an antibacterial activity (resistance genes). Information resulting from this study has already allowed us to propose a plausible biosynthetic pathway (chemical reactions involved in the synthesis of congocidine). Verification of this hypothetical pathway has been undertaken. Finally, genes directing the biosynthesis of distamycin have been isolated and their sequencing is under way.