Researchers at the University of Dundee have developed a computational protocol that predicts the likelihood for any given compound to act as a broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria.

Background

There is an urgent need for new drug candidates to combat antibiotic resistance. The majority of totally or extremely drug-resistant priority pathogens, as defined by the WHO, are Gram-negative. It is widely understood that there is insufficient drug permeation into Gram-negative organisms due to their complex and poorly permeable cell envelope.

The Opportunity 

Dundee researchers have developed an AI technology based on data mining, chemoinformatics and machine learning. The technology has been trained on compounds curated to address the Gram-negative cell wall obstacle. The algorithms are designed to detect and predict broad spectrum antibacterial activity. The technology especially targets novel chemical space by removing known antibiotic compounds and similar structures from the training datasets. In recent tests of the technology, a virtual screening of compound databases has identified about 1,000 new molecules, from around 3M readily synthesisable molecules, which score high on probability for broad spectrum activity. The major molecular features that contribute to the scores are also identified. The method has the potential to be applied to antivirals and other areas of unmet clinical need by varying the training datasets.

Key Benefits

• Gram-negative antibiotic discovery 
• Novel curation process that addresses cell wall permeation 
• Rapid virtual library screening 
• Identification of molecular features that drive permeation 
• Reduce time, cost and failure rates 
• Protocol could extend to antiviral

Commercial Opportunity

This exciting technology is able to pre-screen proprietary and public compound libraries to increase the success rate of anti-infectious drug discovery programmes, thereby reducing time, cost and attrition rates. The University is seeking a development partner for this methodology and contact is welcomed from organisations interested in collaboration for this opportunity.

Researchers at the University of Dundee have developed a novel method for the recombinant production of universal Group A Streptococcus (GAS) glycoconjugate vaccine candidates. This approach allows hijacking of the Protein Glycan Coupling Technology (PCGT) currently used to produce glycoconjugate vaccine candidates for pathogenic bacteria, including Streptococcus pneumoniae. The team has produced the first recombinant GAS ‘dual-hit’ glycoconjugate vaccine candidate system. This method produces high yield and high purity of recombinantly produced GAS rhamnose polysaccharides (RhaPS) conjugated to protein carriers of choice. 

Background

Antimicrobial options for effectively controlling, treating and preventing Streptococcus pyogenes (Group A Streptococcus, GAS) infections are becoming more limited due to emerging antibiotic resistance, pandemic development and the evolution of hyper virulent strains. There is an urgent unmet need for the development of a safe, effective and universal prophylactic vaccine candidate for GAS. GAS kills more than 500,000 people worldwide each year. 

The Opportunity

For a vaccine to be capable of targeting all of >150 different GAS serotypes, a ubiquitous and universally conserved GAS target needs to be identified. The only target that is 100% conserved in all GAS isolates is the Group A Carbohydrate (GAC), a peptidoglycan-anchored rhamnose-polysaccharide (RhaPS) from GAS. The GAC is essential to bacterial survival and contributes to GAS ability to infect the human host. The GAC polyrhamnose (RhaPS) backbone is a validated vaccine candidate protecting in the animal model GAS infections and showed no cross-reactivity with human tissue.
Currently, RhaPS vaccine development has been limited to chemical and enzymatic extraction methods from streptococcal bacteria, as well as chemical conjugation to an acceptor compound. This method is costly for vaccine development as it is both labour intensive and requires many quality control steps. The Dundee research team identified the key priming steps in the biosynthetic pathway of the GAC virulence determinant and have developed a modular production platform compatible with the synthetic production of RhaPS in E. coli. They produce pure RhaPS glycoconjugates via the efficient and low-cost Protein Glycan Coupling Technology (PGCT). The methodology provides a number of novel solutions to producing glycoconjugates of high quality and yield that serve as vaccine candidates to target all GAS serotypes. The platform allows the recombinant conjugation of the polyrhamnose to any acceptor protein of choice and a tightly regulated carbohydrate length to produce high quality and homogenous vaccine candidates. The recombinant approach has thus many advantages to the use of natively produced and extracted RhaPS.
The researchers have recently shown that recombinantly produced RhaPS induce GAS specific antibodies in mice and that RhaPS trigger a carbohydrate specific immune response. This suggests that this method produces vaccines with long-lasting immunity. Preclinical work is now continuing apace with a Wellcome Trust Innovator Award.

Key Benefits

• Synthetic RhaPS 
• Targets across GAS serotypes 
• Uses bulk bacterial fermentation
• High yield & homogeneity 
• Modular production platform
• Expandable platform for human and veterinary pathogens 

IP Status

GB filing 1908528.1Priority date 13 June 2019. PCT publication 17 December 2020.

Commercial Opportunity

The University is seeking investment for a spin out opportunity centred on this technology.