Last week started with a major announcement, and an important opening of a research facility previously sanctioned. The new announcement was for a £100 million building programme for facilities at our Institute for Animal Health at Pirbright. Since the major UK-wide outbreak of foot-and-mouth disease (FMD) in 2001, and subsequent reports such as those by Anderson (twice (PDF)), Beringer, Callaghan, Gilligan (PDF) and Gull (PDF), the value of maintaining research into exotic animal diseases, and preferably concentrating it at a well-constructed world-class site, has been well recognised. For instance, Anderson showed that the costs (PDF) of the 2001 FMD outbreak were some £8,000 million, and an independent report (PDF) showed that pre-emptive action by Philip Mellor and his colleagues at the IAH prevented the incursion of bluetongue disease into the UK at a financial saving (PDF) for one year alone of £485 million – let alone the saving in human and animal misery. We are all really delighted with this new announcement, that will put BBSRC researchers, and the UK as a whole, at the forefront of research into diseases of this type – many of which are viral (such as ‘swine’ flu) and as zoonotic diseases can infect humans as well as animals.
Research on animals and animal cells is an important part of basic biology and biomedicine, and I was pleased to attend the opening, by Science Minister Lord Drayson, of another new facility at our Babraham Institute that will contribute significantly to our resources for carrying it out. The £22 million Biological Support Unit is built to a top-class specification, and came in on time and on budget.
Infectious bacterial diseases remain an important problem, and although – since the invention of antibiotics – pathogenic bacteria lack the terror they once caused, the emergence of strains resistant to existing antibiotics gives considerable cause for concern. It is thus important to understand the basis of antibiotic action, as a means for helping to find new and improved antibiotics.
Now it is easy to assume, given their name, that antibiotics kill bacteria, but actually most of them do not in fact do so, or not directly. Penicillin – a discovery attributed to Fleming, albeit the antibiotic action of fungi was known some 60 years early – does kill bacteria, but only if they were growing. This is because it weakens their cell wall, so that growing (dividing) bacteria explode (a nice movie is here) but non-growing ones are unharmed. Most other antibiotics are in fact only bacteriostatic, i.e. they stop cell growth and division, leaving the immune system to dispose of them in its own time. However, some antibiotics are bactericidal, i.e. they do kill bacteria, even if the bacteria are not trying to divide. It was never obvious to me why this should be so, since simply causing bacteria to cease growth was evidently not of itself bactericidal. A wonderful paper from Jim Collins and his colleagues, that I have somewhat belatedly read, provides much of the answer. As so often, iron is involved, specifically via the Fenton reaction in which poorly liganded ferrous ions reduce the comparatively harmless hydrogen peroxide to the deadly hydroxyl radical.
Based on a previous paper from the same group, Kohanski et al. (2007) reported that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, utilize internal iron liberated from iron-sulfur clusters to promote Fenton-mediated hydroxyl radical formation in bacteria, that such hydroxyl radical generation contributes to the killing efficiency of these lethal drugs (probably via their known ability to damage DNA), and that in contrast antibiotics that are merely bacteriostatic do not cause the production of such hydroxyl radicals. This systems biology approach suggests that there is a common mechanism of iron/hydroxyl-mediated cellular death underlying the action of all classes of bactericidal antibiotics, and opens up many new possibilities for combination therapies based on promoting this kind of activity selectively. “Striking while the iron is hot”, one might say.
- Dwyer, D.J., Kohanski, M.A., Hayete, B., and Collins, J.J. (2007). Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli. Mol. Syst. Biol. 3, 91. Full free text (PDF)
- Kaur, P., Agarwal, S. & Datta, S. (2009). Delineating bacteriostatic and bactericidal targets in mycobacteria using IPTG inducible antisense expression. PLoS One 4, e5923. Full free text (PDF)
- Kell, D. B. (1987). Forces, fluxes and the control of microbial growth and metabolism. The twelfth Fleming lecture. J. Gen. Microbiol. 133, 1651-1665
- Kell, D. B. (2009). Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Medical Genomics 2, 2
- Kohanski, M.A., Dwyer, D.J., Hayete, B., Lawrence, C.A., & Collins, J.J. (2007) A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130, 797-810
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