Award details

Exploring novel binding pockets in DNA gyrase and DNA topoisomerase IV to address antibiotic resistance

Reference	BB/V007041/1
Principal Investigator / Supervisor	Professor Colin Fishwick
Co-Investigators / Co-Supervisors	Dr Martin McPhillie
Institution	University of Leeds
Department	Sch of Chemistry
Funding type	Research
Value (£)	453,274
Status	Current
Type	Research Grant
Start date	01/11/2021
End date	31/10/2024
Duration	36 months

Abstract

DNA gyrase is a type II topoisomerase that can supercoil DNA using the free energy of ATP hydrolysis. It is essential in bacteria but lacking from human cells. Its topoisomerase reaction involves the generation of transient double-stranded breaks in DNA. Interruption of the DNA breakage-reunion step of this reaction can lead to a lethal lesion in bacteria. These features have led to gyrase becoming a well-validated target for antibiotics. Most bacteria also contain a related enzyme, DNA topoisomerase IV, which can also be targeted by antibiotics. Fluoroquinolones (FQs), such as ciprofloxacin, target gyrase and topo IV, and have enjoyed widespread clinical success. However, resistance to FQs has become a serious problem and alternatives are urgently needed. Working with GSK, Sanofi and other partners as part of an EU consortium (ENABLE), we have revealed novel unexploited drug-binding pockets, and compounds (thiophenes and IPYs) that inhibit gyrase and kill bacteria by binding to these pockets. Although the compounds themselves are unlikely to be taken forward to the clinic, this discovery presents us with the opportunity of exploiting these novel pockets to develop new compounds with potential as antibiotics. Using computational modelling methods, new compounds will be designed and synthesised (Leeds). These will be tested in in vitro assays with gyrase and topo IV from key bacterial species (JIC). This information will be fed back to the Leeds team to inform the design of new compounds. Complexes between gyrase/DNA and high-potency compounds will be subject to crystallography to ascertain the binding mode (JIC) and this information will be fed back to the design platform. Such compounds will be further analysed using microbiological assays and preliminary toxicity trials (JIC/Leeds). This programme aims to deliver a fundamental understanding of new drug-binding pockets and new compounds that could be taken forward in the future as potential antibiotics.

Summary

Antimicrobial resistance (AMR) is probably the biggest current threat to human health. Recent estimates (O'Neill Report, 2016) suggest that 10 million people a year could die as a result of AMR by 2050. In addition, the economic cost has been estimated to be between 60 and 100 trillion USD worth of economic output, if antimicrobial drug resistance is not tackled. This AMR problem is compounded by the lack of new antibacterial agents coming onto the market, caused by the loss of profitability of such drugs. Amongst the most successful groups of antibiotics of modern times are the fluoroquinolones (FQs), such as ciprofloxacin. However, these too are subject to increasing AMR and alternatives need to be found. FQs act by targeting DNA gyrase and/or DNA topoisomerase IV, enzymes that are essential in bacteria but absent from human cells. We are working with compounds that also target gyrase but that act in a different way such that cross resistance with FQs can be avoided. Currently these compounds are not suitable as human antibiotics due to issues such as toxicity. Using computational methods, synthetic chemistry, biochemical/biophysical studies, microbiological and toxicology evaluation, and structural work, we aim to develop new, drug-like compounds (i.e. with favourable properties in terms of solubility, potency and size) that retain their antibacterial efficacy but which also have other properties required for drug leads, including low toxicity. At the end of this project, we aim to have identified a new series of antibacterial drug leads that will hold considerable promise for subsequent development.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Microbiology, Structural Biology, Systems Biology
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

Associated awards:

BB/V006983/1 Exploring novel binding pockets in DNA gyrase and DNA topoisomerase IV to address antibiotic resistance

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search