Novel antibacterial compounds
Antibiotics interfere with a particular bacterial function, hampering its growth and spreading. The aminocoumarin and the cyclothialidine type of antibiotics produced by Streptocymes are known to inhibit the activity of DNA gyrases, an enzyme required for maintaining the DNA conformation. The EU-funded ‘Development of new gyrase inhibitors by combinatorial biosynthesis’ (Combigyrase) project took advantage of European expertise in the field to research and develop new drugs that were urgently needed. The project was designed to expand the diversity of potent gyrase inhibitors found in nature by methods of combinatorial biosynthesis. Combinatorial biosynthesis is a new technology that uses genetic manipulation to improve the chemical properties and pharmacological activity of naturally occurring compounds. By modifying the gene cluster responsible for antibiotic production and introducing them into suitable Streptomyces host strains, novel metabolites can be produced. Project partners managed to identify and isolate cyclothialidine genes from micro-organisms producing highly potent antibiotics of the cyclothialidine class. Sequence analysis of the cloned DNA allowed partners to identify several non-ribosomal peptide-synthetase (NRPS) genes and the sequence required for cyclothialidine and biosynthetic intermediates. Furthermore, a gene was identified which could play a role in the modification of cyclothialidine biosynthesis. The combinatorial biosynthesis of antibiotic metabolites used in the Combigyrase project represents a promising method for developing new antibacterial compounds and a great help in our battle against antibiotic resistance.
