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Countering antimicrobial resistance: investigating β-lactamase inhibitors using atomistic simulation and experiment


Project Description

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ for entry in September/October 2020. Students interested in and eligible for this PhD project should contact Dr Marc van der Kamp as soon as possible (, https://vanderkampgroup.wordpress.com). You will also need to complete an application to the GW4 BioMed MRC DTP for an ‘offer of funding’ before the deadline.
DEADLINE: November 25 2019 by 5:00 pm
More information can be found here: View Website: https://www.gw4biomed.ac.uk/doctoral-students/

You do NOT need to apply to the University of Bristol at this stage – only those applicants who are successful in obtaining an offer of funding form the DTP will be required to submit an application to study at Bristol.

Lead supervisor: Dr Marc van der Kamp, School of Biochemistry (Bristol)
Co-supervisors: Dr Jim Spencer (Bristol), Prof Adrian Mulholland (Bristol), Prof Tim Walsh (Cardiff University)

Rising antibiotic resistance is a major problem for human health. Resistance to β-lactams, the single most important antibiotic class, often arises through breakdown by β-lactamases (BLs). Many BL producing bacteria are multi-drug resistant and may cause untreatable infections. A clinically important class of BL inhibitors to combat this resistance are diazabicyclooctanes (DBOs), used together with β-lactams (e.g. avibactam-ceftazidime, relebactam-imipenem) to treat complicated infections. Interestingly, new DBOs in development (e.g. Nacubactam, Zidebactam) show inhibition of penicillin binding proteins (PBPs) as well as BLs, leading to a so-called “enhancer” effect of existing β-lactam antibiotics and possible use as ‘dual mode’ antibiotics.
To inhibit BLs and PBPs, inhibitors form stable covalent acyl-enzyme complexes. Using multi-scale computer simulations, we have calculated the efficiency of acyl-enzyme formation and breakdown, thereby predicting whether individual BLs can confer resistance to specific β-lactams [1] and their susceptibility to BL inhibitors [2]. Structures of key BLs with several inhibitors have been obtained [3].

This multidisciplinary project aims to address why certain DBOs also inhibit PBPs whereas others do not. Computational assays based on multi-scale simulations will be used to assess formation and breakdown of acyl-enzymes formed by a range of DBOs with clinically relevant serine BLs (e.g. KPC-2, OXA-48 and variants) as well as PBPs. This is challenging, as different reaction mechanisms will need to be explored. The accuracy of these assays will be validated by experimental determination of DBO inhibition of example BLs and PBPs using steady-state, stopped- and quenched-flow kinetic methods (Spencer). The BL test set will include new variants identified from an extensive collection of clinical isolates collected worldwide, focusing on regions with endemic resistance (Pakistan, Thailand, Vietnam), and characterised by genomic and phenotypic approaches (Walsh).

The project will provide training in cutting-edge techniques in multiple disciplines (computational chemistry, molecular biology/biochemistry, clinical microbiology/genomics) using state-of-the-art facilities in the context of a highly collaborative AMR research environment. The project will benefit from Bristol’s excellent high-performance computing resources (incl. one of the UK’s largest university computer clusters). The student will be embedded in the Bristol Computational Biochemistry grouping (www.bristol.ac.uk/bcompb) and the Centre for Computational Chemistry (http://www.chm.bris.ac.uk/ccc/).

Insights obtained into DBO inhibition will inform development of new DBOs with desirable characteristics. Synthetically tractable DBO modifications will be identified and evaluated in silico to assess their promise as BL and PBP inhibitors. Potential exploitation will be discussed with companies active in this area. We will also exploit current interest in antimicrobial resistance through public engagement.

Funding Notes

A full studentship will cover UK/EU tuition fees, a training support fee and a stipend (£15,009 p.a. for 2019/20, updated each year) for 3.5 years. UK and EU applicants who have been residing in the UK since September 2017 will be eligible for a full award; a limited number of studentships will be available to EU applicants not meeting the residency requirement. Applicants who are classed as Overseas for tuition fee purposes are not eligible for funding, but can apply for a self-funded studentship. More information on eligibility may be found on the DTP’s website: View Website

References

1. Chudyk EI, Limb MA, Jones C, Spencer J, van der Kamp MW, Mulholland AJ. Chem Commun, 2014, 50, 14736. DOI: 10.1039/c4cc06495j
2. Fritz RA, Alzate-Morales JH, Spencer J, Mulholland AJ, van der Kamp MW. Biochemistry, 2018, 57, 3560. DOI: 10.1021/acs.biochem.8b00480
3. Tooke CL, Hinchliffe P, Lang PA, Mulholland AJ, Brem J, Schofield CJ, Spencer J.
Antimicrob Agents Chemother, 2019, 63, e00564-19. DOI: 10.1128/AAC.00564-19

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