The molecular basis of the action of the antibiotic simocyclinone D8 on DNA gyrase

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

Abstract

Antibiotics are drugs used to treat infections caused by bacteria. Most antibiotics are natural products and many of these are derived originally from soil bacteria (called Actinomycetes). Although antibiotics have generally been very successful over the last 40 years or so, recent years have seen the emergence of antibiotic-resistant bacteria (the so-called 'Superbugs'). These include MRSA (methicillin-resistant Staphylococcus aureus) and C. difficile, which have led to significant concern, particularly in UK hospitals. Unfortunately fewer new antibiotics are coming on the market, raising the prospect of untreatable bacteria diseases in the future. Simocyclinone D8 is a relatively recently discovered antibiotic that is not currently in clinical use. We have been able to show that it targets an enzyme in bacteria (DNA gyrase) by a previously undiscovered mechanism. DNA gyrase has proved to be very successful as a target for existing antibacterials, such as the fluoroquinolone ciprofloxacin. However, the emergence of quinolone resistance has rendered these compounds less effective and therefore we need to search for new ways of targeting DNA gyrase. Therefore our aim is to understand the mechanism of action of simocyclinone in detail in order to reveal principles of drug-target interaction that will be applicable to other systems. We anticipate that this knowledge will provide information that will be used, particularly in the pharmaceutical industry, in the design of more-potent, more-specific antibiotics that will avoid the resistance problems that we are currently encountering.

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