Pre-clinical research to treat bacteria leading to sight loss and hospitalisation

Brief Lay Background

In the UK there are approximately 10-12,000 cases a year of microbial keratitis and outcomes often remain poor despite prolonged periods of antimicrobial treatment and in many cases hospitalisation. Pseudomonas aeruginosa is one of the main microorganisms associated with microbial keratitis, particularly in contact lens wearers. The incidence of P. aeruginosa microbial keratitis is approximately 4-5 per 100,000 in high income and 20 per 100,000 in low-resource settings. There has also been a notable increase in antimicrobial resistance and it is recognised by the WHO as an essential microorganism requiring research.

What problem/knowledge gap does it help address

Corneal opacification (cloudiness of the cornea) is the sixth leading cause of global blindness, accounting for an estimated 3.2% (0.5%-7.2%) of 36million cases of blindness. The incidence of microbial keratitis is 2.6-40.3/100,000 in UK to 113/100,000 in India. P. aeruginosa, which produce Exotoxin U (ExoU),are a dominant variant of the bacteria and are associated with poor outcomes and more antimicrobial resistance.

Patients with severe microbial keratitis caused by P. aeruginosa often require hospitalisation or are dependent on intensive home support. Treatment depends on broad spectrum antimicrobials, which have little effect on bacterial toxins. There is, therefore, a need for inhibitors of ExoU to improve outcomes.

An advantage of reducing bacterial virulence, is that it gives antimicrobials time to eradicate bacteria but with less damage to the host. Inhibitors of bacterial toxins reduce damage without interfering with the host’s response, control of infection or increasing risk of recurrent disease. Not only reducing acute tissue destruction, ExoU Inhibitors might also reduce toxin associated inflammation, allowing a more appropriate immune response.

Aim of the research project

To evaluate and select the best inhibitors of the toxin ExoU of P. aeruginosa with the aim of repurposing them for treatment of microbial keratitis.

Key procedures/objectives

1. Identify inhibitors of ExoU.
2. Test in model systems those that show potential for repurposing.
3. Determine dosing schedule and effectiveness of inhibitors.

Potential impact on people with sight loss

The ultimate success of this project will be a reduction in morbidity and improved outcomes in microbial keratitis. If the severity of the infection could be reduced and controlled by these inhibitors for this specific exotoxin, this would reduce loss of vision, dependency on antimicrobials and reduce hospitalisation. This will also establish a pathway for the development of other inhibitors for additional bacteria commonly involved in microbial keratitis such as Staphylococcus aureus or Streptococcus pneumonia. In addition, provision of anti-ExoU compounds may have a direct role in the treatment of acute and ventilator pneumonia.