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Developing new antibiotic compounds: Dual-targeting inhibitors

The views expressed are those of the author and are not necessarily those of Scientific American.


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A lot of the research that gets highlighted on this blog is academic, providing fascinating insights into bacterial behaviour and potential antibiotic targets. I was excited, therefore, to have the opportunity to highlight some industrial research, looking at developing new antibiotic compounds against a broad-spectrum range of bacteria. In particular this research concentrates on potential inhibitors that target both the action of DNA-gyrase and DNA-topoisomerase IV, both of which are vital for DNA replication. If the bacterial DNA is unable to replicate, then the bacteria cannot produce offspring and the infection cannot take hold.

The research isolated a range of interesting compounds, labelled GP-1 to GP-12. These compounds were tested for their ability to kill the bacteria Burkholderia pseudomalia, a naturally occurring tropical/sub-tropical bacteria. Time-kill assays were performed, measuring how many bacteria both compounds killed over time, and showing a decrease in the number of bacteria after 24 hours treatment with the compounds. They also tested the compounds in mice infected with the B. pseudomalia strains, looking at the number of bacteria found in the spleen and lungs following treatment.

This crystal structure shows the drug candidate molecule GP-12 binding to one of its cellular targets, Gyrase-B, from pathogenic E. faecalis. (c) Trius Therapeutics, Inc.

To get a further picture of how these compounds were carrying out their antibiotic activity, the company also carried out research on the pharmokinetics of the drug, i.e how it works within a body. In order to discover how stable the compounds were (i.e whether they just break down inside a body) they were incubated with animal or human liver microsomes and appropriate co-factors at 37 degrees C for up to 60 min. To study the behaviour of the compounds within a body, plasma and tissue were collected from animals treated with the drug compounds, to see where they ended up, and how they behaved in the blood. The results showed compatible binding to blood proteins in both mice and human samples, which is important as it means that further mouse research is more likely to produce results relevant for humans. The drug dispersed well throughout the body, particularly appearing in the liver and kidneys (not surprising as they tend to excrete antibiotics) and only minimal amounts appearing briefly in the brain, which is also good.

The final part of the research involved testing the drugs ability to destroy pathogens in mouse models. The researchers tested the response of GP1-8 on two important clinical strains; S. pneumoniae (a Gram positive bacteria) and E. coli (a Gram negative bacteria). Excitingly, the results showed that infections from both Gram negative and Gram positive bacteria could be cleared – infections ranging from bacteria in the lung (in the case of S. pneumoniae) and in the kidneys and thigh muscle (in the case of E. coli).

Drug candidates GP-2 and GP-4 tested against A. baumannii, a clinical pathogen. Activity of these two compounds is compared to other antibiotics, ciprofloxacin (CIP), gentamicin (GEN), imipenem (IPM), and cefepime (FEP). (c) Trius Therapeutics, Inc.

There’s plenty more research to be done before these compounds start moving into actual clinical trials, but it is interesting to see the potential for new broad-spectrum antibiotics – i.e compounds that can attack a range of bacteria rather than just a few isolated species. The great thing about industrial research is that with the money and infrastructure behind the research, there is the potential for interesting compounds to be shunted through to clinical trials very efficiently, resulting in the eventual production of new pharmaceutical products.

Thanks to Trius Therapeutics for letting me have a sneaky peak at their posters and research. Further details of their research can be found here. Please note that I am not in any way economically affiliated with this company.

S.E. Gould About the Author: A biochemist with a love of microbiology, the Lab Rat enjoys exploring, reading about and writing about bacteria. Having finally managed to tear herself away from university, she now works for a small company in Cambridge where she turns data into manageable words and awesome graphs. Follow on Twitter @labratting.

The views expressed are those of the author and are not necessarily those of Scientific American.





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