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  Synthesis and Screening of Inhibitors for β–Lactamases

   College of Health and Life Sciences

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  Dr D Rathbone, Dr J Cox  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Owing to the overuse of penicillins, cephalosporins and carbapenems, β-lactam resistance has become a major public health problem. Many Gram-negative bacteria have developed or acquired a sub-set of β-lactamases known as carbapenemases that destroy a swathe of the world’s antibiotics of last resort. The carbapenemases may be divided roughly into two types: those having a serine residue in the active site that is essential to the mechanism of action and those that are Zn(II)-dependent metallo-β-lactamases (MBLs). The most clinically-important sub-set of MBL carbapenemases is known as New Delhi metallo-β-lactamase-1 (NDM-1). The active site of this enzyme contains a metal centre comprising two Zn(II) ions. A water molecule coordinated between the two Zn(II) ions is activated and facilitates the attack of hydroxide ion onto the lactam carbonyl of any bound bicyclic β-lactam antibiotic. This results in ring-opening and concomitant neutralisation of the compound (Kim et al, 2013; Watkins et al, 2013; González et al, 2015). Potent inhibitors of NDM-1 have yet to be reported. If selective, potent and non-toxic inhibitors of NDM-1 and other β-lactamases could be discovered then there is the possibility to develop a drug against this enzyme that would then allow the carbapenems to be used again.

The aim of this project is to prepare, characterise and screen potential inhibitors for β-lactamases. The molecules under consideration will mimic the known substrates for the various β-lactamases but contain a functional group that will derivatise the active side cysteine (in the case of serine β-lactamases) or react with the activated water molecule held between the two zinc ions in the NDM-1 active site to produce a product that will then go on to tighter binding with the zinc ions. The project will involve synthetic chemistry and screening of the target compounds using a rapid TLC-based method developed by the Cox group (Lopeman et al, 2020).

Estimated yearly cost of consumables

£4,000 per year

Person Specification

A Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution)

Submitting an application

As part of the application, you will need to supply:

·        A copy of your current CV

·        Copies of your academic qualifications for your Bachelor degree, and Masters degree (if studied); this should include both certificates and transcripts, and must be translated in to English

·        A research proposal statement*

·        Two academic references

·        Proof of your English Language proficiency

Details of how to submit your application can be found here

*The application must be accompanied by a “research proposal” statement. An original proposal is not required as the initial scope of the project has been defined, candidates should take this opportunity to detail how their knowledge and experience will benefit the project and should also be accompanied by a brief review of relevant research literature.

Please include the supervisor’s name and project title in your Personal Statement.

If you require further information about the application process please contact the Postgraduate Admissions team at [Email Address Removed]

Biological Sciences (4)

Funding Notes

There is no funding for this project.


González, M. M., Kosmopoulou, M., Mojica, M. F., Castillo, V., Hinchliffe, P., Pettinati, L., Brem, J., Schofield, C. J., Mahler, G., Bonomo, R. A., Llarrull, L. I., Spencer, J., and Vila, A. J. (2015) Bisthiazolidines: A substrate-mimicking scaffold as an inhibitor of the NDM-1 carbapenemase. ACS Infectious Diseases. 1: 544-554.
Kim, Y., Cunningham, M. A., Mire, J., Tesar, C., Sacchettini, J., and Joachimiak, A. (2013) NDM-1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism. The FASEB Journal. 27: 1917–1927.
Lopeman, R. C., Harrison, J., Rathbone, D., Desai, M., Lambert, P. & Cox, J. A. G., 2020, Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus, Scientific Reports. 10, 1, 928.
Watkins R. R., Papp-Wallace, K. M., Drawz, S. M., and Bonomo, R. A. (2013) Novel β-lactamase inhibitors: a therapeutic hope against the scourge of multidrug resistance. Frontiers in Microbiology. 4: 392
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