An EU-funded project has found a potential new way to target drug-resistant bacteria, and it is hoped that the initiative's drug discovery platform will lead to more ground-breaking discoveries - with the potential to save lives.
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The ENABLE project is working to advance the development of potential antibiotics against gram-negative bacteria, such as Escherichia coli. Antimicrobial resistance (AMR) has led to a marked increase in the number of untreatable infections, which represents a significant global health threat. It is estimated that antibiotic-resistant bacteria kill 25 000 people in the EU every year, and costs the economy €1.5 billion.
A key facilitating element in this has been the project's drug discovery platform, which enables teams of scientists to test and optimise promising molecules.
"In this way, ENABLE is working to progress new antibiotics to treat gram-negative infections one step closer to patients," explains Robert Stavenger of GlaxoSmithKline Research and Development in the UK, who has been involved in the ENABLE project since its inception.
The research team recently found new compounds that inhibit a bacterial enzyme called DNA gyrase, which means that bacteria can no longer replicate their DNA and spread in an infected patient. While compounds that act on bacterial DNA gyrase are already available on the market, these antibiotics act against DNA gyrase in a similar way. This means that bacterial resistance can render the entire class of antibiotics redundant.
This factor is what makes the new discovery an exciting development in the ongoing battle against antimicrobial resistance - the compounds inhibit DNA gyrase in a completely different way. Instead of blocking DNA gyrase, it binds to the enzyme in a way that still prevents it from functioning normally. Researchers were able to study this mechanism of inhibition in depth, demonstrating the effectiveness of strong collaboration between researchers and industrial partners in the pharmaceutical sector. "Although further research on this compound will not continue due to its toxicity, this is a promising first step," says Stavenger.
A platform for change
ENABLE is part of the Innovative Medicines Initiative (IMI)'s 'New Drugs for Bad Bugs' (ND4BB) programme, a pan-European effort to tackle the AMR threat. IMI is a public-private partnership funded jointly by the EU and the European pharmaceutical industry. ND4BB currently comprises seven projects, of which ENABLE is one.
"The project has evaluated over 70 applications for antibacterial programmes so far and funded 16," says Stavenger. "It is possible that new antibiotics will be delivered in the future if these programmes are successful. The project is also helping to train up the next generation of antibacterial drug discovery scientists."
Industry and research organisations can join the ENABLE project as partners and access the drug development platform in order to advance molecules through the drug development process. Novel applications will be received until 2018. Programme owners retain full ownership of their molecules to ensure they are free to optimally develop programmes in the future.
The early success of the project is a positive sign given the global threat posed by the proliferation of multi-drug resistant bacteria. By 2020 the project hopes to have begun preclinical and phase 1 clinical studies (i.e. early testing safety on humans) of at least one promising antimicrobial candidate.
"In addition to decreasing morbidity and mortality from life threatening infections such as bacterial pneumonia, effective antibiotics make other lifesaving medical treatments like complex surgeries and chemotherapy treatment possible," says Stavenger. "But with the rise in bacteria that are resistant to most or all available antibiotics, such treatments may no longer be possible."