Antivirulence treatment for microbial keratitis

Brief lay background

Glaucoma is caused by a combination of adverse external factors, increasing age, and inherited genetic susceptibility. Genetic studies have identified hundreds of small genetic changes causing susceptibility to glaucoma, enabling us to understand some mechanisms involved.

However genetic risk factors cannot be changed, and novel treatments can only indirectly target the pathways causing disease. Much of glaucoma risk is caused by non-heritable, or “environmental” factors. These, and genetic factors often result in changes in metabolites, which are chemicals found in blood and eye tissues and are involved in biological and metabolic processes.

What problem/knowledge gap does it help address

Pseudomonas aeruginosa is one of the most common types of bacteria that cause microbial keratitis. There is an urgent need to develop new treatments due to a recent rise in antibiotic-resistant strains of these bacteria. 

In Pseudomonas infections with poor outcomes, the bacteria inject a toxin called Exotoxin U (ExoU) into body cells – including cells of the immune system sent to fight the infection. Developing drugs that can block the activity of ExoU could provide an effective new treatment to reduce the damage caused by these infections.  

Aim of the research project

To investigate 25 promising drug molecules that inhibit ExoU – specifically looking at their ability to reduce tissue damage in a selection of laboratory models.

Key procedures/objectives

1. Test the effectiveness of potential inhibitors of ExoU in relevant cell models – at different concentrations and combinations.
2. Determine the best concentration of ExoU inhibitors in human corneas attached to an artificial glass model of the front part of the eye.
3. Evaluate the effectiveness of ExoU inhibitors in pig corneas infected with Pseudomonas.
4. Assess the effects of the two best ExoU inhibitors and protocols in a mouse model of corneal infection. 

Potential impact on people with sight loss

Ultimately, this research could lead to the development of new drugs that can help to reduce corneal scarring and loss of vision in patients with severe microbial keratitis.

In addition, it is hoped that using these drugs will reduce the dependence on antibiotics and the associated risk of drug resistance.