Beating the global threat of resistant bacteria

Discuva

Discuva is a Cambridge UK-based specialty drug discovery company, focusing on the creation of next generation targeted antimicrobials against new emerging and drug-resistant bacterial pathogens. The company’s SATIN platforms includes the routine profiling of the effect of antimicrobial agents on gene expression in bacteria using next generation sequencing (NGS) and bioinformatics technologies.

Eagle Genomics helped Discuva, a drug discovery company focused on antimicrobials, to create tools and databases to support the development of new antibiotics to tackle resistance in bacteria.

Objectives

Antibiotic resistance is a growing problem, and one that is causing increasing concern worldwide. Many infections, such as gonorrhoea, are becoming resistant to the antibiotics of last resort, and there are rising levels of hospital-acquired resistant infections. Resistant infections also cause problems in surgical patients, and in the management of people with chronic diseases such as cystic fibrosis.

Discuva, an antimicrobial-focused company based in Cambridge, UK, uses its SATIN (Selective Antibiotic Target Identification) drug discovery platform to find narrow-spectrum antibiotics that are effective against individual species of multidrug-resistant bacteria, including the Gram-negative bacteria, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli and Neisseria gonorrhoeae. These can cause a range of hospital and community-acquired infections including sepsis, respiratory infections and urinary tract infections. Discuva’s approach is finding antibiotics with novel and unrelated mechanisms of action, which will slow the development of resistance. These antibiotics are already moving through their drug discovery pipeline, where their properties are being refined for human use. Eagle Genomics improved Discuva’s research in three steps.

Approach

GeneDisplay Tool & Database

Discuva’s researchers profile the effect of antimicrobial agents on millions of different bespoke mutations in bacteria to find molecular targets and genes associated with resistance, using a next generation sequencing (NGS) assay. These results are generated as a collection of files and the platform then creates a report comparing the effect of the compound on the bacteria with controls, using a tool called GeneDisplay. The analysis supports selection of the best compounds for optimisation by Discuva’s in-house medicinal chemistry team. The existing GeneDisplay tool performed well enough to meet the company’s existing needs, but when Discuva planned an increase in the number of studies, needing a ten-fold increase in the rate of profiling, the tool was no longer able to meet the company’s needs.

Discuva needed to find a way to track, store and display the increased amount of information arising from the additional studies, and called in Eagle Genomics to help. Eagle’s expert team enhanced the GeneDisplay tool, and built a new database as a single repository for all the data. This includes options to load the sequencing data from the pipeline into the database with a single click and search it using a series of different variables via a web front end. The data is then displayed in an interactive graph.

Antibiotic Dendrograms

Discuva had a set of tools that created antibiotic effect dendrograms from gene expression data. These allowed researchers to understand more about the degree of relationships between potential compounds based on their mechanisms of action, and use this information to determine the novelty of a molecule. However, this was a two-step process, with one tool generating a file, and the second creating the dendrogram, and required expert input from Discuva’s bioinformatics team.

Using the database developed for project one, Eagle Genomics created a tool that could pull data out of the database and build a matrix to examine the relationships between compounds. This used existing information on their mechanism of action in different bacteria. Users enter search variables into a simple web front end and this generates a web link, taking the user to a page that generates a dendrogram. This is a visual representation of the closeness of relationships between the mechanisms of action, helping researchers to determine the risk and rate of development of cross-resistance.

Faster Report Creation

Discuva’s researchers used results from GeneDisplay to generate reports based on gene expression data generated from the bacteria’s responses to each compound. These are for internal research purposes and for its collaborators, but the process was lengthy, requiring manual cutting, pasting and editing.

As a follow up to first challenge, Eagle Genomics adapted GeneDisplay to be able to populate the reports with a single click, based on a number of different variables defined by the users, including information from the database, and data from reports on related compounds and target and resistance genes. This creates a first draft that is faster to adapt and edit, includes more information, and is organised in a more useful way, for example highlighting target or resistance information.