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Characterisation and engineering of the biosynthetic pathways of two model pyrrole amide antibiotics, congocidine and distamycin


With natural product-derived (or inspired) molecules used as drugs in almost all branches of medicine, natural products play a key role in our pharmacopoeia. Among natural product producers, Streptomyces are remarkable for their ability to produce an unriv alled range of chemically diverse secondary metabolites, displaying a wide range of biological activities such as antibiotic, immunosuppressant or antitumor activities. Pyrrole amides constitute a family of natural products produced by Streptomyces and rel ated actinobacteria. Their ability to bind DNA in the minor groove confer them a variety of biological activities. Moreover, two of the best known members of the family, congocidine and distamycin, have attracted considerable attention as they have been sh own to bind DNA in a sequence-specific manner. The aim of this project is to elucidate the biosynthetic pathways of two related pyrrole amides, congocidine and distamycin, and to use the knowledge gained from these studies to engineer analogues of these mo lecules and generate new biologically active molecules. The congocidine biosynthetic gene cluster, which has already been identified in the host institution, represents the first known pyrrole amide biosynthetic gene cluster and shows promising novel featu res for combinatorial biosynthesis.

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Rue Georges Clemenceau

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