Nucleic Acid Synthesis and Cell Division in Model Pathogenic Bacteria

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The rise of antibiotic resistance, particularly in hospitals, over recent years represents a huge financial burden on the health system, in addition to the personal costs to the patient infected. Over the last 60 years, we have become accustomed to the availability of antibiotics that can effectively treat most, if not all, bacterial infections. Today, this is not the case, and some bacteria in hospitals are resistant to all therapeutically useful antibiotics. The costs of drug development are very considerable; from the financial perspective of a pharmaceutical company, the de novo development of new antibiotics is not attractive because they are drugs that are only used for a short period. Recoupment of development costs takes a long time. As a result, very few new antibiotics are currently in development, and many of the newer ones are the result of academic efforts and subsequent formation of spin-out companies that develop new drugs through to phase 1 trials. The need for new, and effective, antibiotic therapies is pressing. We propose to identify and validate the use of key essential biological processes as targets for the development of new antimicrobial agents in two important hospital pathogens. Staphylococcus aureus is a well known and established pathogen that is the number one cause of hospital acquired (nosocomial) infections. Acinetobacter sp. is a relatively new problem in nosocomial infections, but is growing in importance due to the startling rate at which it is able to acquire resistance to antibiotics. In both organisms, we intend to target essential protein-protein interactions involved in DNA replication (duplication of genetic material), transcription (production of a genetic message), and cell division. The targeting of protein-protein interactions, rather than the enzymic activity of a protein provides a novel and unexploited avenue for antibacterial development with great potential for success.