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The resurrection of antibiotics: finding new synthesis routes to fight antimicrobial resistance

 17 June 2019   Research News

By the year 2050, 10 million people will die because of antimicrobial resistance (AMR) every year. That is the equivalent of one death every three seconds. AMR is quickly becoming a serious problem and the pressure to find alternative options is building fast.

One of the most prescribed class of antibiotics are called fluoroquinolones. They kill bacteria within an infection by interfering with enzymes that are critical to bacterial cell survival. These enzymes are part of the topoisomerase family, specifically DNA gyrase and topoisomerase IV – which are responsible for the unwinding and rewinding of the DNA.

The fluoroquinolone antibiotics bind to and block the action of the DNA gyrase enzyme. But due to the amount of antibiotics being prescribed and the number of people who don’t complete the full course, there is more and more resistance to antibiotics. Specifically, in this example, it causes mutations to occur in the gyrase enzyme that prevents the antibiotics binding and stopping the enzymatic action in the bacterial cell. So, are these antibiotics becoming redundant or can they be given a new lease of life?

Resurrecting the fluoroquinolone class of antibiotics

Attempts to find completely new antibiotics to prescribe are not progressing at the rates that we need to take action. So, perhaps we might be able to use what we already have to bind with the mutated gyrase enzyme – specifically the ones that are no longer sensitive to the fluoroquinolone antibiotics?

In a study published in Medicinal Chemistry Communication, researchers in the Cell Cycle group at the LMS, in collaboration with researchers from the Department of Chemistry at Imperial College London, reported a new route for synthesising a type of naturally occurring antibiotic called nybomycin.

Nybomycins are a family of naturally occurring antibiotics found in soil bacteria, and haven’t been extensively studied. But preliminary studies suggest that the antibiotics are able to kill bacterial cells that are resistant to fluoroquinolones. That may be because they can target the binding sites of the gyrase enzyme that are resistant to fluoroquinolones.

This recent study disclosed a new route for the synthesis of the nybomycin series and confirmed the effectiveness of this series against fluoroquinolone-resistant bacteria. The synthesised nybomycins derivatives were added to fluoroquinolone-resistant bacteria and were able to successfully kill them. This means that, potentially, in the future fluoroquinolones and nybomycins could be used as a combination therapy to combat the rise of AMR.

PhD student Oliver Bardell-Cox, first author of this publication, discussed finding the right route for nybomycin synthesis:

“There were a few reported routes in the literature that we tried initially that were long and inefficient from raw materials to synthesised products. They also proved to be capricious and were not easily reproducible. So, we re-designed the synthesis, changing a few of the key molecules involved to make the whole process much more scalable and efficient. Now we have a synthetic route that can really help to drive forwards a really important series of antibiotics.”

Luis Aragon, Head of the Cell Cycle group at the LMS, discussed the next steps for this research:Luis Aragon

“Nybomycins are an antibiotic that are not yet ready for humans. There are a lot of chemical complications that we need to improve before they could be used in treatments. Specifically, we want to play with the geometry to make it more ‘drug-like’. In it’s natural state, nybomycins are very planar which means it is very easy for all the molecules to sit on top of each other and stay in that formation. We need to make them more three-dimensional to prevent them sticking together because if you want to be able to take them as a pill, then they need to be soluble. Having a molecule that is not planar will help with that process. We also want to look more into the biology and understand why nybomycins have this activity and not an activity more like the fluoroquinolones.”

 

‘Synthetic studies on the reverse antibiotic natural products, the nybomycins’ was published in Medicinal Chemistry Communications on 24 May. Read the article here.