Smart technology speeds up development of antibiotics

Discuva uses groundbreaking technologies to address antibiotic resistance. The Cambridge-based biotechnology company was established in 2009 and is focusing on building a pipeline of new antibiotics to target Gram-negative bacteria such as E. coli, A. baumanii, K. pneumoniae, and P. aeruginosa, each responsible for causing sepsis as well as serious urinary tract and respiratory infections. Discuva’s founders, including David Williams, Clive Mason, and John Wain, developed the company’s proprietary SATIN (Selective Antibiotic Target IdentificatioN) platform. This microbial genetics, sequencing and bioinformatics platform enables fast and precise identification and optimisation of new classes of antibiotics to fight bacterial pathogens. “A disruptive approach for a de-novo antibiotic discovery programme was exactly what Roche was looking for when we entered into a discovery and development partnership with Discuva in spring 2014,” said Michael Crowley, PhD, Global Head of Innovation Partnering at Roche.

Discuva’s SATIN platform utilises large bespoke bacterial transposon libraries with very high transposon insertion density. They consist of a culture strain of the bacterial pathogen, with each cell in the population containing a single transposon integrated into the chromosome at a random position. The different transposons are engineered to either disrupt a gene at the insertion site within the gene or to elevate the expression of the gene adjacent to the insertion site. The libraries are grown in the presence and absence of compounds that slow, halt or stop bacterial growth. Those bacteria having the transposon “at the right site” will be able to survive the pressure of the antibiotic compound based on the corresponding disrupted or promoted gene. In order to locate the position of each transposon in each bacterium, the libraries are analysed at the population level with Next Generation Sequencing methods (NGS). This also allows insertion frequencies to be determined.

The enormous data sets generated by NGS are further processed using specialised machine-learning and bioinformatics software, providing a detailed understanding of the compound’s mechanisms of action and possible routes of resistance. “The SATIN technology is allowing us to visualise for the first time the genome-wide response a bacteria has to an antibiotic – this information enables not only the discovery process but also informs ultimately on clinical utility,” said David Williams, CEO of Discuva.

Roche and Discuva met for the first time in Chicago at the 2013 BIO International Convention, a time when Roche was seeking innovative technologies to re-enter antibiotic research. Eager then - as we are today - to invest in the discovery and development of pathogen-specific and broad-spectrum antibiotics, Roche found Discuva’s SATIN platform highly promising. Not only did the approach allow access to highly differentiated screening technologies and molecular microbiology capabilities, it also complemented Roche’s in-house capabilities. Discuva, in turn, was searching for a strong partner from the pharmaceutical industry with sound discovery and clinical development expertise in the field of infectious diseases. “It seemed like the perfect match,” said Barbara Lueckel, PhD, Head of Early Stage Partnering, “however, due to the complexity of the platform, we firstly carried out a pilot project.”

This trial demonstrated the full breadth of the SATIN technology and led to the initiation of a multi-year partnership that was extended in early 2017. “From day one of the partnership, we felt this was a true collaboration based on mutual respect for the contributions from both parties and a shared passion to deliver much-needed new antibiotics to patients”, said Discuva’s Director of Biology, Clive Mason. John Young, Global Head Infectious Diseases Discovery at Roche pRED said: "The collaboration has fully leveraged the complementary expertise of Roche and Discuva to deliver several exciting antibiotic programs to our pipeline." To date, the collaboration has produced promising preclinical data for broad spectrum as well as pathogen-specific antibiotic compounds targeting Gram-negative multidrug-resistant bacteria.