Two heads are better than one in a new mode of antibiotic action.

An antibiotic that binds to a well-established target in a novel and unexpected way could be the inspiration for designing new, more potent antibiotic drugs.

"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 (JIC). Professor Innes is the lead author on the antibiotic research that is soon to be published in the journal Science.

The JIC is an institute of the BBSRC.


The antibiotic molecule, simocyclinone D8 (SD8), is a natural product made by soil bacteria, that has, to date, been somewhat underexploited as a drug entity. This can, in part, be explained by the fact that SD8 itself does not easily penetrate bacterial cells, but it raises the possibility of finding other antibiotic molecules that fit into the binding pockets (see the paragraphs below), or designing molecules that work by this mechanism but that penetrate cells more easily.


The novel antibiotic molecule exerts its effect by slotting into pockets at the surface of a bacterial enzyme, DNA gyrase, therby inhibiting its activity. Gyrase is an enzyme that is essential for the survival and growth of bacteria. It is not, however, present in humans and therefore represents an ideal, and already established, target for antibiotic development. Professor Maxwell commented that: "If you can knock out this enzyme, you have a potential new drug"


The molecule SD8 has two heads that dock into separate pockets in DNA gyrase, and exert a synergistic effect some 100 times more powerful than exhibited by the blockade of either pocket individually. Neither pocket has previously represented a target for antibacterial drug development. Although bacteria could develop resistance to compounds with this mode of action, it might be expected that occupation of two separate, dissimilar sites would be less likely to induce resistance compared with other antibiotics.


"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," explains Professor Maxwell.


"You could say that this is a case of two heads being better than one."



The current method of antibiotic drug discovery is to screen protein targets or bacteria against vast libraries of compounds. Any hits are investigated in more detail.


The research reported in Science is a significant advance as the scientists already know in detail how the molecule works. Understanding the mode of action will facilitate the future development of optimized compounds, that may in the future represent important drug entities.


'A crystal structure of the bifunctional antibiotic, simocyclinone D8, bound to DNA gyrase' by M Edwards (JIC), R Flatman (JIC), L Mitchenall (JIC), C Stevenson (JIC), T Le (JIC), T Clarke (University of East Anglia), A McKay (University College London), H-P Fiedler (Eberhard Karls Universität Tübingen) , M Buttner (JIC), D Lawson (JIC) and A Maxwell (JIC) will be published in Science on December 3rd and was funded through JIC's core strategic grant from the BBSRC.


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Novel Technologies  •  Pharmacology/ Therapeutics  •  Target Identification/ Validation


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