Protein antibiotics for the treatment of Pseudomonas aeruginosa lung infection

Antibiotic resistance poses a dire threat to the population and if no new antibiotics are developed we may soon find ourselves with no useful therapeutics to treat a range of potentially fatal bacterial infections. Unfortunately, few new antibiotics have been developed in recent years and for some bacteria there are almost no therapeutic options remaining. As the prevalence of infections caused by multidrug resistant bacteria is rapidly increasing this problem may soon become a modern health crisis.
A major problem in the development of antibiotics is identifying suitable molecules within bacteria to target with novel molecules. This is one reason why, even with great advances in our understanding of bacteria such as the ability to sequence their genomes, most efforts to develop new antibiotics have failed. However, in contrast to our own ability to create effective antibiotics, other microorganisms are extremely good at this. This is a direct consequence of evolution by natural selection where the ability to produce an effective antibiotic and thus kill bacteria that are competing for recourses is strongly selected for.
We are working on a group of antibiotics that have evolved to kill only bacteria very closely related to the producing bacterium. Although they do not kill all bacteria, they have evolved to kill the bacteria they do target with unmatched potency. We intend to develop a highly targeted antibiotic as a therapeutic for the treatment of a specific bacterium (Pseudomonas aeruginosa) that is the major cause of death in people with cystic fibrosis (CF). Since we know exactly the type of bacteria that is responsible for these infections a highly targeted approach should work well. This is an area of great unmet clinical need, since the antibiotics that are currently used to treat these infections frequently fail and so most CF patients still die before they reach 30.
The aim of this work is to develop a highly targeted antibiotic to treat Pseudomonas aeruginosa infections that we have demonstrated is highly effective against this organism. To achieve this we will develop methods to produce and formulate this molecule as a therapeutic that can be used in humans and undertake extensive safety testing to demonstrate it is safe for use by people with CF.

Chronic lung infection with Pseudomonas aeruginosa (PA) and the consequent progressive decline in lung function is the major cause of mortality in cystic fibrosis (CF) patients. The antibiotics that are currently available for the treatment of PA infection are inadequate and there is an urgent need to develop new therapeutic options to increase the current median age at death of CF patients, which is 29 years.
The University of Glasgow team led by Dr Dan Walker have demonstrated that highly selective protein antibiotics, known as pyocins, show potent activity against PA in the planktonic and biofilm states and this potency translates directly to the treatment of PA in an in vivo model of lung infection. Therefore, pyocins have the potential to transform our ability to treat chronic PA lung infection and offer a therapeutic strategy that could extend the lifespan of CF patients. Dr Walker's team have identified a lead pyocin candidate, pyocin S5, which displays strong efficacy against diverse strains of PA in an in vivo model of lung infection. In this model, pyocin S5 displays a potency several orders of magnitude in excess of tobramycin, which is widely used for the treatment of PA lung infection in CF patients.
The aim of the DPFS programme is to optimise methods for the formulation, delivery and manufacture of the lead pyocin and to generate preclinical toxicology and safety pharmacology data for the administration of pyocin S5 by nebulisation. The data generated during the course of this award will provide the basis for post-DPFS clinical trial authorisation (CTA) application to perform a first-in-man study in patients with cystic fibrosis.

The primary beneficiaries will be patients with cystic fibrosis (CF) who have a chronic P. aeruginosa (PA) lung infection. CF is the most common fatal genetic disease among Caucasians with over 10,000 patients in the UK and a total of 70,000 patients in Europe and the USA. In the UK in 2013, 51 % of adult CF patients had a PA lung infection. PA lung infection is the major proven cause of mortality in this patient group whose mean age at death is 29 years. For CF patients, pyocin S5 will improve their quality of life and extend lifespan through its ability to effectively kill PA. Beyond CF, these benefits will also accrue to other patient groups such as the estimated 3 million UK and 12.7 million US sufferers of COPD who also encounter PA infections. The proposed DPFS program will take 36 months to complete and deliver a data package sufficient for a clinical trial authorisation application. Assuming success in the clinic and regulatory approval then pyocin S5 could be available to patients in 2025.
As pyocin S5 is potentially the first in a novel class of antibiotics, in the longer term, direct economic and societal benefits will derive from the development of related protein antibiotics, which will reduce morbidity and mortality from bacterial infections and will reduce costs associated with failed antibiotic treatment. The true economic cost of not having effective antibiotics is probably difficult to estimate, since this would not only affect our ability to treat primary bacterial infections, but would also impinge on our ability to treat of a range of chronic conditions where antibiotics form an integral part of the treatment regime. In addition, it would affect our ability to perform a range of invasive surgical interventions, where antibiotics are routinely used to prevent infection. Biotechnology and pharmaceutical companies will benefit directly from our research through the identification of a new class of antibiotics that can be developed as therapeutics.