Public Funding for Defenition Limited

Gonorrhoea may soon become untreatable and the discovery of new antibiotic therapeutics acting via novel biological pathways is urgently needed. Caused by the pathogen Neisseria gonorrhoeae, gonorrhoea is a sexually transmitted infection (STI) estimated to have an annual global incidence of 79 million. Although STIs are not fatal diseases, they cause significant complications including pelvic inflammatory disease, infertility, chronic pelvic pain complications in pregnancy, neurological and cardiovascular disease and an increase in HIV susceptibility and infectivity. Public Health England reported that there were 45,000 cases of infectious gonorrhoea in England in 2017, a 22% increase from the previous year. Worryingly, N. gonorrhoeae has developed resistance to standard antibiotics and in 2017, the WHO warned that resistance to the current last-line therapy (a dual therapy of ceftriaxone/azithromycin) was emerging and that treatment failure is likely to become widespread in the future. Both in 2014 and in 2018, strains of N. gonorrhoeae that are resistant to all antimicrobial agents have been identified in the UK. While there is a consensus around the need to discover truly new classes of antibiotics, acting via novel biological pathways, the current clinical pipeline for gonorrhoea is only constituted of three drugs, all of them targeting already precedented biological targets. Therefore, there is a significant risk that these drugs will be subject to existing resistance mechanisms. Flap endonuclease enzymes (FENs) represent a new class of target for the development of novel antibiotics with a low resistance profile. FENs are highly conserved enzymes that are essential for DNA replication and repair, and for the maintenance of genomic stability. While knockout gene studies have shown that FEN activity is essential for bacterial life, their high degree of conservation and central role in DNA replication limits the scope for resistance to emerge as a consequence of mutation. DeFENition Ltd is a drug-discovery spin-out from the University of Sheffield developing an innovative class of antibiotics. Its pipeline is based on small molecules that inhibit bacterial FENs, a novel antibacterial target that we are not aware that any other group is working on. Additionally, DeFENition Ltd aims to develop inhibitors with narrow spectrum of action, an approach that contrasts with the majority of antibacterials used and in development. In this SBRI project, we will develop further a class of potent Neisseria gonorrhoeae FEN small molecule inhibitors that have been discovered at DeFENition. The aim is to demonstrate that FEN inhibition leads to antibacterial activity and to generate physicochemical and ADMET properties to identify compounds with a profile enabling further development.

The development and spread of antimicrobial resistance is a complex issue to which the costs of inaction are huge. Today, 700,000 people die of resistant infections every year and it is estimated that by 2050, 10 million lives a year are at risk due to the rise of drug-resistant infections. Additionally, it has been shown that the antibiotics that have been recently approved, and those at various stages of development, show a mismatch between what the world needs, given emerging levels of drug resistance, and the size and quality of the pipeline to address this growing challenge. In particular, there is a critical need for new classes of antibiotics, acting via novel biological pathways. Bacterial flap endonucleases (FENs) are highly conserved enzymes that are essential for DNA replication and repair and the maintenance of genomic stability in pathogenic bacteria. Since loss of FEN activity is fatal to the target organism, they represent a new class of target for the development of novel, high-value antibiotics with a low resistance profile. This project, undertaken by DeFENition Ltd, a newly formed biotech, in partnership with the Sheffield University, is aiming at identifying and developing bacterial FENs inhibitors for use as antibiotic agents.