New hope for antibiotic advance
Partly EU-funded research published this week in the journal Science describes the newly determined structure of a key antibiotic that binds to a well-established target in a novel and unexpected way. The discovery could inspire a new range of more powerful antibacterial drugs. The study was carried out at the John Innes Centre of the BBSRC (Biotechnology and Biological Sciences Research Council) in the UK, and formed part of the CombiGyrase project ('Development of new gyrase inhibitors by combinatorial biosynthesis'), funded at EUR 1.56 million under the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6). The antibiotic molecule, called simocyclinone D8 (SD8), slots into pockets in the surface of a bacterial enzyme called DNA gyrase and inhibits its activity. DNA gyrase, which helps wind and unwind DNA, is essential for the growth and survival of bacteria. DNA gyrase is not, however, naturally present in the human body and therefore it is an important target for antibiotics. Two groups of gyrase-specific antibacterial agents are quinolones and aminocoumarins. The research team analysed the structure of a third type, called simocyclinones. These consist of both an aminocoumarin and polyketide group. The team found that each of these groups binds to a separate pocket on the gyrase and is relatively weak by itself, but together they form a powerful force to inhibit DNA binding. The newly discovered antibiotic molecule has two heads that dock into separate pockets of the DNA gyrase enzyme. Together these are 100 times more powerful than they are individually. Neither of these pockets has been exploited before by antibiotic drugs targeting this enzyme and the possibility of bacterial resistance may be less than with other antibiotics. 'A completely new way to beat bacteria is an exciting find at a time when resistance to existing antibiotics is growing,' said Professor Tony Maxwell from the John Innes Centre, and lead author of the study. 'If you can knock out this enzyme, you have a potential new drug.' 'The fact that there are two pockets means that it might require simultaneous mutations in both pockets for the bacteria to acquire full resistance to the drug, which is much less likely,' explained Professor Maxwell. 'You could say that this is a case of two heads being better than one.' SD8 is a natural product that is made by soil bacteria. The determination of its structure opens the possibility of finding other molecules that fit into the binding pockets, or of designing molecules that work in the same way, but penetrate cells more easily. SD8 could also be modified or new compounds could be developed to design new antibiotic drugs.
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