Re tooling for microbiology: A novel screening method for antibacterials

Fellowship for Lisa Titcomb

Bacterial infections caused by pathogens resistant to many antibiotics are now frequently a serious clinical problem. In Europe, antibacterial-resistant infections kill nearly 25,000 patients and represent a total cost of approximately £1.5 billion per year. In response, the Chief Medical Officer of the United Kingdom termed antibacterial resistance to be "a major area of concern" and suggested that the UK government facilitate global action, especially with respect to the development of novel antibacterials. However, the cost involved in developing and testing any new drug is large. That, coupled with the fact that an antibacterial drug is only given for a limited time, makes research in this area unattractive for pharmaceutical companies. The proposed research employs synthetic microbiology to develop a biological screening platform that will significantly reduce these costs while increasing the rate at which compounds from pre-existing libraries can be assessed for antibacterial activity.

A two-component regulatory system works via a stimulus-response mechanism that allows an organism to sense and respond to changes in different environmental conditions. Two-component systems (TCSs) are commonly found in bacteria and are absent in humans, which makes them an ideal target for an antibacterial agent. Initially, a natural products library provided by LifeArc (a charity originating from the government funded Medical Research Council) will be screened to identify small molecules that interact with the receptors in a specific class of TCSs known as sensor histidine kinases (SHKs). Often a critical step in bacterial virulence is the perception of a stimulus by an SHK that then triggers the production of virulence factors that enable the bacteria to flourish. Any compounds shown to prevent stimulus perception by interacting with the SHKs would be used to identify further classes of small molecule libraries that could be usefully screened. Over the longer term, this information could be used to initiate structure-based drug design.

The proposed research has the potential to offer a new screening method and class of antibacterial targets. Ultimately, it could lead to the development of novel therapeutic treatments for bacterial infections.

This Fellowship was supported by the Daphne Jackson Trust and provided Dr Lisa Titcomb with an opportunity to retain as a microbiologist.