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COMBIGYRASE Sintesi della relazione

Project ID: 503466
Finanziato nell'ambito di: FP6-LIFESCIHEALTH
Paese: Germany

Final Report Summary - COMBIGYRASE (Development of new gyrase inhibitors by combinatorial biosynthesis)

A constant threat to the population of the European Union is the ever-increasing problem of antibiotic resistance. Widespread use of antibiotics has led to the emergence of antibiotic-resistant strains. The increase and spread of resistance are matters of serious public health concern worldwide. For example, vancomycin has long been considered as the solution to methicillin-resistant Staphylococcus aureus (MRSA) infections, but vancomycin-resistant strains of S. aureus have emerged. The risk of infection increases with a prolonged hospital stay, and so does failure of antibiotic therapy because of multidrug resistance.

In the decade preceding the project, many pharmaceutical companies reduced their efforts to discover new anti-infectives, particularly new antibiotics, and redirected their research and development (R&D) efforts to other fields perceived as more profitable. However, infectious diseases represent a large market with high unmet medical needs, as shown by the strong interest of many large pharmaceutical companies to acquire novel antibiotics once they have reached late development/registration stages.

The EU, including the most recent Member States, possesses a long tradition in basic and applied research on antibiotic-producing microorganisms in both academic and industrial institutions. European scientists have made seminal contributions in several disciplines, ranging from bacterial taxonomy to natural product chemistry, from molecular genetics to bacterial physiology. These disciplines have now been complemented by combinatorial chemistry, genomics and combinatorial biosynthesis. This provides a step change in our ability to produce new bioactive compounds capable of addressing serious medical needs.

The bacterial enzyme DNA gyrase is well validated as a target for a number of antibacterial compounds. The COMBIGYRASE consortium took advantage of the expertise that existed across Europe to research and develop new drugs that were urgently needed. It represented an ideal platform to expand the diversity of potent gyrase inhibitors found in nature by methods of combinatorial biosynthesis. Combinatorial biosynthesis is a novel technology that uses genetic manipulation to improve the chemical properties and pharmacological activity of naturally occurring compounds.

From micro-organisms producing highly potent antibiotics of the cyclothialidine class, several cosmids containing cyclothialidine genes were identified. Partial sequence of the cloned DNA region allowed partners to identify several non-ribosomal peptide-synthetase (NRPS) genes. Several mutants in NRPS genes were generated, which were unable to produce cyclothialidine and biosynthetic intermediates.

Interestingly, a gene was identified coding for a protein with high similarity to phthalate dioxygenases. This protein could play a role in the modification of the resorcinol ring in cyclothialidine biosynthesis.

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