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Fighting Antimicrobial Resistance

The pipeline for antibiotic discovery is all but dry with global pharmaceuticals market failing to produce drugs to respond to unmet medical needs. There is an urgent need for new approaches to old targets (that are known to work) and to provide wholly new solutions. We focus our activities on developing multiple targets that can be hit simultaneously by a single inhibitor. The classic example of this is penicillin that targets multiple penicillin-binding-proteins (PBPs) involved in cell wall biosynthesis. We have developed multidisciplinary teams to produce wholly new assays to probe PBP activity as well as new assays for tRNA synthetase activity. We recognise the need to work closely with industry and to equip the next generation of researchers in the multidisciplinary skills, insight and inspiration to take this important challenge on.

Background

Antibiotics such as penicillin and successive generations of β-lactams, tetracylines and macrolides have underpinned the development of modern medicine. These antibiotics, respectively target the final stage of bacterial cell wall biosynthesis, specifically the structural polymer peptidoglycan (PG) or protein biosynthesis. Both represent important targets historically and in the future for antibiotic discovery. We have active research programmes looking at both areas.

A particular focus is upon PG biosynthesis which is polymerized (via transglycosylase, TG activity) and cross-linked (via transpeptidase, TP activity) by a family of enzymes, the penicillin-binding-proteins (PBPs) with multiple under- or un-characterised domains. Yet, given their importance we know little about how PBPs interact with their natural substrates, precisely what these substrates are, nor, how polymerization and cross-linking is co-ordinated and controlled at the biochemical, structural and cellular levels, and all importantly precisely how β-lactam antibiotics interfere with this process. This is now crucial, as resistance to β-lactam antibiotics has emerged. Resistance rarely involves alteration to the multiple PBP targets of penicillin found in all bacteria. As such PBPs remain attractive to the future development of either new variants of β-lactams that evade resistance mechanisms or wholly new classes of inhibitors.

This principle of multi-targeting is a concept we are also exploring as a route to novel antibiotics with an entirely different set of enzymes involved in protein biosynthesis, the tRNA synthetases. These enzymes append individual amino acids to tRNAs required for protein synthesis. The importance of this process to cellular activity is vital and we are exploring the ways in which these enzymes edit inevitable mistakes in their mechanism as a route to a novel antimicrobial strategy

Impact

At Warwick we have brought together a multidisciplinary team, within a wider Warwick activity WAMIC, that works closely with industry to develop new biochemical tools and reagents to probe PBP activity, establish new assays and probe PBP vulnerability. We have already developed first in class quantitative assays for the targets of penicillin and tRNA synthetases. Recently we have converted these to industry standard formats to enable high-throughput screens that will identify chemical inhibitors and the commencement of antibiotic discovery programs. Our biochemical and structural biology approaches to developing multi-targeting inhibitors will militate against the rapid emergence of resistance found recently when focussing upon disabling single targets.

Future

We are involved in UK and USA driven policy development, AMR discovery charities, and alongside well funded research programs are developing new multidisciplinary doctoral training programs to tackle AMR, with UK and international academic and industry partnerships. Such innovations are crucial if we are to see new discoveries that will help underpin an effective pipeline of antibiotics for future generations.

E.Coli


Principal Investigators:


WAMIC, the Warwick Antimicrobial Interdisciplinary Centre, brings together cross-campus expertise to tackle antimicrobial resistance.

Researchers from Life Sciences, Physics, Maths, Medicine, Chemistry, Engineering and Social Sciences are combining efforts to develop a range of solutions, including: diagnostics, synthetic therapies, behaviour change, natural products, phages and predictive modelling.

Find out more: www.warwick.ac.uk/WAMIC