New research that maps the 3D interactions of fluoroquinolones with the DNA machinery of the tuberculosis bacterium reveals clues that could help drug developers make these old anti-TB drugs more effective – even against resistant forms of the infectious lung disease.
Image credit: Tim Blower
Two papers on the research – both involving a team from the Johns Hopkins University School of Medicine in Baltimore, MD – are published in the Proceedings of the National Academy of Sciences.
Quinolones – a class of commonly used broad-spectrum synthetic antibiotics – were first developed in the early 1960s. They were followed a few years later by more potent versions called fluoroquinolones – made by adding a fluorine atom to the base molecule.
All quinolones kill bacteria in the same way, by blocking an enzyme called gyrase that is essential for DNA synthesis. Without gyrase, the bacterial DNA falls apart.
But, as is happening with many classes of antibiotics, these old drugs are rapidly losing their effectiveness as drug-resistant strains of disease bacteria – including those that cause tuberculosis (TB) – increase.
However, on a more optimistic note, James Berger, first author and professor of biophysics and biophysical chemistry, says:
“Our work helps show that we need not – and indeed should not – give up on fluoroquinolones, a longtime weapon in the fight against disease-causing bacteria in general.”
He says their work highlights several promising possibilities for revamping fluoroquinolones into versions that might even work against extensively drug-resistant TB.
Using X-ray crystallography, Prof. Berger and colleagues mapped the detailed 3D structure of the drugs interacting with gyrase in the TB bacterium and discovered clues as to why some drugs are more potent against the infectious lung disease than others.
They generated 3D atom-by-atom models of interactions between TB’s gyrase and five different fluoroquinolones, including a new one called 8-methyl-moxifloxacin.
The models helped them view a “pocket” inside the enzyme that the drugs sit in and see how the drugs could potentially interact with it at two different sites.
At one of the sites inside the enzyme, the team found it is possible – in the case of the TB version of gyrase – for a protein building block to be swapped for one that makes fluoroquinolones less effective against TB.
And the researchers also found – to their surprise – that none of the drugs they tested latched onto the other site at all.
Prof. Berger says these findings point to untapped potential for creating fluoroquinolone derivatives that bind to both sites and thereby increase their interactions with gyrase.
Also, because the bacteria may develop resistance by changing one of the sites – but far less likely to do so by changing both sites – then drugs that address both sites are more likely to retain their potency, suggest the authors.
However, the biggest surprise of all came when the team discovered that the fluoroquinolone with the strongest anti-TB effect did not use the two sites at all – they exerted their power through their direct effect on DNA inside the gyrase.
Prof. Berger concludes:
“This result means the fluoroquinolones aren’t working in the most straightforward way, and that’s a challenge for drug developers. We have to rethink the chemistry of these drugs, but doing so will likely open up new avenues for improvements.”
TB infects around a third of the world’s population, and in 2013, it claimed 1.5 million lives. Nearly half a million global cases of TB are thought to be multidrug resistant.
Meanwhile, Medical News Today recently learned that some drugs already approved for the treatment of conditions such as parasite infection and cancer could be adapted into antibiotics to treat staph and tuberculosis infections.