The molecular basis of action of the toxin Microcin B17 on DNA gyrase

Lead Research Organisation: John Innes Centre
Department Name: Contracts Office

Abstract

We are in danger of heading for a crisis in infectious bacterial diseases. The combined effects of multi-drug-resistant bacterial infections, such as MRSA and C. difficile, and the lack of new antibiotics being produced by pharmaceutical companies, means that academic labs need to make a more significant contribution to solving this problem. We are studying an enzyme from bacteria called DNA gyrase, which is already the target for antibiotics such as Cipro (ciprofloxacin), the drug used to combat anthrax during the scare in the USA in 2001. Unfortunately, due to resistance problems, Cipro is no longer as effective as it was and the search is on for antibiotics to replace it. Microcin B17 (MccB17) is a toxin produced by bacteria to kill other bacteria, and it works in a manner similar to Cipro but is unlikely to be affected by the same resistance problems. We aim to understand the molecular details of how MccB17 works such that this information can be used in the future design of new antibiotics that can potentially replace Cipro.
The overall objective is to understand the interaction of MccB17 with in molecular detail and to enable the future exploitation of this knowledge to develop novel anti-bacterial agents.
This will contribute to our knowledge-base of ligand-protein interactions, reveal a novel mechanism of inhibition of gyrase and have the potential to contribute to the development of future antibacterial agents. The specific objectives are:
1. To determine the mode of interaction of MccB17 with gyrase using a combination of molecular genetic, chemical and structural (NMR and crystallography) approaches.
2. To produce fragments and derivatives of MccB17, using genetic and chemical methods, in order to generate structure-activity relationship information about MccB17 action.

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