One of the most important antibiotics used in hospitals is a natural compound discovered in the 1950's. 'But what nature made isn't necessarily an optimized medicine to use in the human body,' says Professor of Biological Chemistry Nathaniel Martin. That's why a group of Leiden researchers is making a chemistry-based improved version of this antibiotic. They received an NWO NACTAR funding to further develop it.
Vancomycin has been used in hospitals for the last fifty years in the same form it is found in nature. 'It's a molecule that is produced by certain microorganisms in soil,' says Martin. 'But the microorganisms that produce vancomycin in nature, didn't optimize its activity for use in the human body. Therefore, we shouldn't assume that the natural compound is the best for treating human infections.'
'We shouldn't assume that the natural compound is the best for treating human infections'
Taking that as a starting point, former PhD candidate Emma van Groesen used chemistry-based approaches to introduce small structural modifications to the vancomycin molecule. 'We made around hundred different variants using a specific chemical modification that we developed. Using this strategy, Emma identified a compound that is a lot more active against bacteria than vancomycin.'
Potential antibiotic named after a Leiden PhD candidate
The new compound got the name EVG7. 'It's named after that PhD candidate Emma who worked on it. EVG are her initials and number seven as it is the seventh compound in the series she made.' The potential new antibiotic gives great results in the lab. And even more importantly: it can effectively cure infections in animal models. 'It even seems to work against really serious pathogens like MRSA, the famous hospital bacteria that is resistant to antibiotics.'
To further establish the therapeutic potential of EVG7, Martin and Elma Mons, a postdoc in his group now leading the project, are working together with the research group of pharmacologist Coen van Hasselt (LACDR). Together they received an NWO NACTAR funding that they will use to work towards human trials. 'We need more research to further validate the safety of the molecule,' says Martin. 'That is something Van Hasselt's group will contribute to. We are experts in making and doing the preliminary tests of these types of molecules, but they better understand how molecules behave when you inject them in a body. So it's a perfect collaboration in which we will use the expertise of both our labs'
Finding the optimal dose
Van Hasselt's lab will further study the pharmacology of EVG7, which is important as it determines in what way EVG7 should ultimately be used in patients. 'Should it be one shot every day or multiple, for example,' says Van Hasselt. 'We will investigate how the EVG7 distributes to different tissues where the infection may occur and how the antibiotic eventually gets removed from the body. These are things that not only vary from drug to drug, but also from patient to patient.'
'It is even working against bacteria that are resistant to vancomycin'
Before going into a human trial, the dosing schedule and effective dose needs to be on point. 'If you don't give enough, you might not treat the infection. But if you give too much, it can have a toxic effect,' Van Hasselt explains. 'And with certain concentrations you are perhaps more likely to evolve resistance. So a very important aspect of developing a new drug is finding the perfect balance.'
Overcoming unwanted side-effects and resistance
In the long term, Martin and Van Hasselt aim to replace vancomycin with EVG7 as the standard antibiotic in the clinic. 'Apart from being more effective, EVG7 also seems to have less side effects,' says Martin. 'Vancomycin often causes kidney damage or other damage to cells. As EVG7 is way more active, we can use much lower doses of it.'
Another problem with many current antibiotics is the high rates of resistance. 'We also understand how EVG7 is targeting bacterial cells and why it does so more effectively than vancomycin. Because EVG7 binds more tightly to bacteria, it is even working against bacteria that are resistant to vancomycin.'
Doing the work of a pharma company
'It is quite unique to see an antibiotic compound being developed in an academic context,' Van Hasselt says. 'For most potential medicines, a pharma company would partner to do the pre-clinical development. But there are only a few companies who are still working on antibiotics. That is partly because of the resistance problem. If you spend a billion euros to develop an antibiotic and within 10 years bacteria are resistant to it, your drug is no longer useful. That's quite a big financial risk.'
The researchers will therefore use the NACTAR funding to do what the pharma companies would normally do for them. They hope to have the research ready for human trials in a few years. When the Leiden team has proven the effectiveness of the antibiotic in detail, pharma companies will be more likely to jump in. 'So I would say that we are working on quite a unique research program,' Martin en Van Hasselt conclude.
Text and image: Inge van Dijck
