KOMM: FutureMDR - A novel antimicrobial to combat multi drug resistant infectious diseases

For years the number of lives lost due to multidrug resistant pathogens increases. It is estimated that currently this already causes up to 50,000 lives in Europe and the US alone. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE) were recently pinpointed by WHO to be the main target for development of new antibiotics acting on Gram-positive multi-resistant bacteria. At SINTEF we are passionate to develop new therapies to increase our prowess against resistant pathogens. In the Trondheim fjord we have found many never discovered marine bacteria, some of which naturally produce yet undiscovered antibiotics. In previous work we discovered that one of these shows a lot of promise as a novel drug against both MRSA and VRE. The development is still at an early stage, but through this project we hope to show the effectiveness of this compound in a suitable model, which is an important milestone in eventually finding its way towards the clinic. The project has followed the proposed research plan. We have sequenced the strain, isolated the gene cluster responsible for production of the compound. This cluster has now been cloned int E. coli where the goal is to transfer this cluster to two alternative streptomyces host for heterologous production. This technology can ease future production and furthermore open the opportunity to make new derivatives of this compound through genetic engineering of the gene cluster. We have also worked with optimising the production in the wildtype strain and based on this produced enough material for the main tasks in the project. We have developed new methods for isolation and purification of the compound. With these procedures we have purified both the main compound and a structurally related compound to high purity. The two compounds have been tested in antimicrobial assays targeting MRSA and VRE strains, and in extended toxicity tests using relevant cell-based assays.