Targetting Penicillin Binding Proteins with dual targetting non-beta lactam antibiotics and Fragment based drug discovery

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

The development and response to Antimicrobial Resistance (AMR) is now widely understood to be a global healthcare emergency. It is widely acknowledged in academia and industry that next generation antibiotic drugs are mostly likely to come from new approaches to inhibiting existing, validated antibiotic drug targets. Outside the bacterial cytoplasmic membrane, there is a sugar-based polymer called peptidoglycan (PG) crosslinked by peptide bridges, which gives the cell wall strength, rigidity, cell shape characteristics and is a scaffold for a multitude of other molecular structures. The formation of PG is performed by a group of enzymes called penicillin binding proteins (PBPs) which are responsible for formation of the sugar backbone and its crosslinking by peptide bridges and are thus well established targets for antibiotics. Disruptions of the PG structure itself or inhibition of the synthesising enzymes by antibiotics, results in cell lysis or cessation of cell growth. Generations of penicillin-based antibiotics have been used clinically to interfere with the crosslinking activity of these enzymes and have been backbone of antimicrobial therapy for many decades. However, resistance to these drugs has occurred by a variety of mechanisms including the recruitment and production of enzymes, which degrade the penicillin chemical structure before it can reach its target. Our project will seek to study and evaluate these enzymes with a series of non-penicillin based compounds, which show promise for next generation antibiotics. In addition, we will use state of the art methods to evaluate the potential of using chemical fragments to build novel inhibitor species to these important cell wall biosynthetic proteins. This project will advance our knowledge of these proteins and contribute to the evaluation and development of next generation antibiotics.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
1642916 Studentship BB/M01116X/1 05/10/2015 30/09/2019 Carmina Micelli
 
Description Conference Travel Fund
Amount £500 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 09/2017
 
Description Oxfrod chemistry 
Organisation University of Oxford
Department Chemistry Research Laboratory
Country United Kingdom 
Sector Academic/University 
PI Contribution We have discussed this project and set up a collaboration with Professor Chris Schofield at Oxford to look at the affinity of beta-lactam dimers and polymers with Beta-lactamase enzymes.
Collaborator Contribution They will provide access to equipment and reagents to support this collaboration as well as host the student
Impact too early
Start Year 2017
 
Description Antimicrobial resistance awareness 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I have been involved in a number of events during the annual Antimicrobial Resistance (AMR) Awareness week. In 2016, I have volunteered in a primary school based in Birmingham delivering classes regarding the problem of the spread of multi-drug resistant bacteria and strategies to prevent or reduce the spread of infections, by following simple guidelines. Classes have been supported by practical activities. In 2017, I have volunteered at Warwick University, the audience was manly represented by undergraduates and they have been involved in both real and virtual games, aimed at raising awareness about AMR and research going on at Warwick University to address this global problem.
Year(s) Of Engagement Activity 2016,2017
 
Description Science gala 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The science gala event took place at Warwick University on the 30th January 2019, and it was an open public event where PhD students and academics from scientific disciplines of the university could showcase their research, in a friendly and entertaining manner to easily reach a general audience of any age.
It was for me a fantastic opportunity to engage with the general public, and pupils in particular, and master my communication skills so that my research work could be understood by anyone out of the field.
My activity consisted in showing 3D structures of proteins by using the Augment app on iPads, and explaining the function and importance of studying those proteins for the discovery of new drugs. Overall, this activity was enjoyed by both children, who were amused by the 3D representation of proteins, and adults who were keen to learn about structural biology.
Year(s) Of Engagement Activity 2019
URL https://warwick.ac.uk/fac/cross_fac/xmas/impact/xmas_scientist_experienceb/science_gala_2019/