The antibacterial drug MGB-BP3: from discovery to clinical trial

It goes without saying now that there is a severe risk to health world wide because of the continued emergence of resistance of bacteria to many of the currently available antibacterial drugs. About 12 years ago at Strathclyde we began a project to see whether it would be possible to transform the oligoamide natural products, distamycin (1) and netropsin (2), into useful antibiotics by modifying their structures so that toxicity and unwanted biological activity was removed and selective, high antibiotic activity obtained. These natural products were well known to bind to the minor groove of DNA and details of the configuration of binding were known from X-ray crystallography [1,2]. A firm basis therefore existed for the design of new minor groove binding ligands. The research plan was to introduce additional hydrophobic components into the ligands so that binding to the non-polar regions of the minor groove could be obtained and so that the physicochemical properties of the new compounds be made more drug-like than those of distamycin and netropsin.