Professor Laura Piddock introduces work done by the research team and the Institute of Microbiology and Infection at the University of Birmingham.
Duration: 03.51 mins
Speaker
S1 Professor Laura Piddock, Deputy Director, Institute of Microbiology and Infection
S2 Liam Redgrave, PhD Student
S3 Sam Sutton, Medical Student
S4 Dr Mark Webber, Senior Research Fellow
Transcript
S1 Fluoroquinolones are synthetic chemicals and antibiotics such as [Suprafoxin] are one of the most widely used antibiotics worldwide. When Fluoroquinolones were launched in the late 1980s it was widely believed that Fluoroquinolone-resistant bacteria would not emerge. Unfortunately, within months Fluoroquinolone-resistant bacteria emerged both in animals and in people and some of these led to clinical failures of treatment.
S2 To understand how quinolones and Fluoroquinolones work we’ve first got to understand how topoisomerase normally function. Imagine you’ve got two pieces of DNA running in parallel to one another. topoisomerase will take hold of both of these pieces of DNA and create a double stranded break in one of the pieces. It will then pass the other piece through, re-seal the break and then let both pieces of DNA go. This process is essential for the processes of cell division and for DNA replication. Quinolones and Fluoroquinolones inter-collate with the DNA enzyme complex and prevent the double stranded break from being re-sealed. This then leads to a build-up of double stranded breaks and eventually results in cell death.
S3 The popularity of Fluoroquinolones in the clinical setting has unfortunately correlated with an increase in the number of clinically resistant isolates. In the UK, e-coli has a right and percentage of resistance to Fluoroquinolones, compared to other strains. For example, since 2001 the percentage of Fluoroquinolone-resistant e-coli has increased from 6% to a staggering 16.6%. Such a magnitude of increase has really impacted on prescribing practices. For example, NICE now recommend Fluoroquinolones as second line agents in an attempt to improve their efficacy. These measures may be responsible for a drop in the rate of pseudomonas aeruginosa and klebsiella pneumoniae isolates, seen in the UK. However, resistance rates still remain high and overall are a problem and other strains such as quinolone resistant neisseria gonorrhoea are now becoming an emerging problem.
S4 As Sam has described, Fluoroquinolone resistance has occurred many times in many pathogenic species in response to exposure to quinolone drugs. However, there is evidence that for some, globally epidemic strains that are clonal, being Fluoroquinolone resistance has actually been really important to their emergence and spread. This includes MRSA, e-coli and clostridium difficile strains. One of the reasons this may have occurred is that some mechanisms of Fluoroquinolone resistance have been found to give a low level broad protection to other classes of drugs. Now this means that the bacteria have a broad protection which can give them a competitive advantage under some circumstances.
S1 Bacteria become resistant to Fluoroquinolones via several different mechanisms. Some mutations affect the interaction of the drug with the target protein and others influence how much drug resides within the bacterial cell, so affects uptake and increases influx. The latter mechanism not only affects Fluoroquinolone antibiotics but many different types of drugs, including Beta-lactams which are also widely used in clinical medicine. As new topoisomerase inhibitors are developed, an understanding of mechanisms of resistance is fundamental so as to minimise the selection of resistant bacteria in the future.
End of recording