Safer Aminoglycoside Therapeutics by Biosynthetic Engineering

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Bacterial infections in hospital patients can lead to sepsis, in which an overwhelming infection of the bloodstream by toxin-producing bacteria becomes life-threatening. Very few new antibiotics are being developed, and so the established antibiotic gentamicin, discovered over 40 years ago, is likely to remain a vital mainstay in efforts to combat sepsis. Unfortunately there are real dangers associated with its use: a large percentage of patients treated with gentamicin, or related antibiotics, develop acute kidney failure (nephrotoxicity). The drug can also cause irreversible hearing loss (ototoxicity). Treatment is very costly because patients have to be closely monitored to minimise these severe side-effects. Sustained efforts are being made to research ways of minimising the side-effects of gentamicin, by altering the dosing strategy for example; and to understand the biochemical mechanisms by which the kidney and the inner ear are damaged. Unfortunately all the gentamicin used clinically is a mixture of compounds and different batches of commercial gentamicin have different amounts of each component. The individual components can be separated on a small scale but it has not been commercially viable to do this on the scale needed. It was believed that all components were equally effective and equally toxic, but in 2006 researchers in the USA re-tested each of the main components (known as C1, C1a, C2, and C2a) and showed that, surprisingly, purified component C2 is fully effective as an antibiotic but not nephrotoxic at all (at least in rats). The aim of this project is to build on the success of our previous MRC-supported research aimed at deciphering all of the individual steps in the late stages of gentamicin biosynthesis. We now think that the best prospect for obtaining C2 by fermentation is to use as a feedstock the widely commercially available precursor called G418. However, we still need to deconvolute the role of key individual enzymes in this part of the pathway. The ready availability of such monocomponent gentamicins would encourage potentially safer formulations of the antibiotic to be tested. Since gentamicins and related aminoglycosides are also promising agents for the correction of certain human genetic diseases, such as cystic fibrosis and the muscle-wasting disease Duchenne muscular dystrophy, there could be wider medical benefits too.