Bicyclic peptides: targeting toxins and pathogens to accelerate anti-infective discovery

Lead Research Organisation: University of Warwick
Department Name: Warwick Medical School

Abstract

This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address important applied biomedical research questions in priority areas aligned with industry. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.

Project:
Bacterial toxins are responsible for a wide variety of human diseases. Increasing prevalence of antibiotic resistance creates further difficulties in the effective treatment of toxigenic bacteria. However, the discovery of novel antibacterial drugs is a major challenge in the R&D process. The dwindling output from High Content Screening of large pharmaceutical company compound collections illustrates that small molecule libraries are focussed on chemistry suitable for mammalian targets and lack compounds with structural features typical of successful antibiotics. Antitoxins are therapeutic agents that reduce symptoms in patients that have been exposed to a toxin. Typically, antitoxins are polyclonal antisera harvested from large animals immunized with inactivated toxin. More recently, some specific antitoxin therapies have been developed using one or more antitoxin monoclonal antibodies (mAbs). However, both antisera and mAbs can be difficult and expensive to produce economically at scale, usually require long development times and often have problematic quality control, shelf-life and safety issues. To date, small molecule approaches to drug these toxins have been unsuccessful so new strategies to develop and prepare antitoxins are urgently needed. In this project, a collaboration between the Dowson group (University of Warwick) and Bicycle Therapeutics Ltd, the student will examine the potential of bicyclic peptides (Bicycles) either as standalone antitoxins or combined with other independently identified antibacterial Bicycles, identified to well validated bacterial targets, in combination as an antitoxin/antibacterial (AT/AB). The initial focus will be to develop antitoxins against Streptococcus pneumoniae toxin Pneumolysin and Staphylococcus aureus Alpha-Toxin and Clumping Factor A alongside other antibacterial targets such as the essential transpeptidase and transglycosylase domains of penicillin-binding-proteins (PBPs), which are involved in peptidoglycan biosynthesis.

Publications

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