Award details

The development of novel caged bata-lactam antibiotics: tools for the study of bacterial resistance by time-resolved IR spectroscopy

Reference	BB/C50446X/1
Principal Investigator / Supervisor	Dr John Snaith
Co-Investigators / Co-Supervisors	Professor C Wharton
Institution	University of Birmingham
Department	School of Chemistry
Funding type	Research
Value (£)	184,456
Status	Completed
Type	Research Grant
Start date	20/10/2004
End date	19/04/2008
Duration	42 months

Abstract

Antibiotic resistance is a serious problem for those animals and humans with a compromised immune system. Some 0.5M people are potentially at risk at any time and the cost is greater than 1.5B GBP, while some 7500 directly attributable deaths result. The problem of antibiotic resistance can be combatted in two ways. Either new targets can be sought or well established but now ineffective antibiotics can be revitalised. We propose the latter, since penicillins are safe and well tolerated by patients. Validation of new drugs should be relatively quick and inexpensive. A detailed knowledge at the atomic level of the enzyme catalysed reaction pathways for antibiotic action and the resistance process is required if a re-design is to be achieved. We propose to develop new photolabile caged b-lactam antibiotics for use in conjunction with fast IR spectroscopy in studies of selected transpeptidases (targets of b-lactam antibiotics) and b-lactamases that destroy them. These cages will allow us to initiate reaction in less than 1 ms using a laser flash, enabling us to follow turnover by time-resolved IR spectroscopy. The photolabile protecting groups that we will develop for this study will be based around the existing dimethoxynitrobenzyl (DMNB), carboxynitrobenzyl (CNB) and benzoin derivatives, but modified to overcome some of the limitations of these systems, most notably poor water solubility and/or undesirably low excitation wavelengths. Our photolabile protecting groups will be used to cage a range of b-lactam antibiotics, including penicillins and cephalosporins, and we will study the kinetics of photolysis of these caged antibiotics in solution. We will then go on to demonstrate that we can perform photolysis to release the free b-lactams in the presence of transpeptidases and b-lactamases, allowing us to follow their hydrolysis by IR spectroscopy. The development of improved caging groups will impact widely on the biological sciences, providing technology to underpinthe study of fast biological processes by a variety of techniques, including optical spectroscopy, time-resolved X-ray crystallography, and voltage measurements. The modifications proposed will lead to a range of protecting groups with good water solubility, fast photolysis kinetics and high quantum yield at a range of wavelengths, suitable for the caging and release of carboxylic acids under very mild, biologically compatible conditions.

Summary

unavailable

Committee	Closed Committee - Engineering & Biological Systems (EBS)
Research Topics	Industrial Biotechnology, Microbiology, Pharmaceuticals, Technology and Methods Development
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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