Antimicrobial resistance is a major public health threat, endangering modern medicine and threatening to send us back to a time when people routinely die of untreatable and uncontrollable infections. Every year, 25,000 deaths in Europe alone are caused by drug-resistant infections, two-thirds due to Gram-negative bacteria such as Escherichia coli. Resistance already exists to the only three drugs that are effective against multi-resistant strains of Staphylococcus aureus (MRSA), and the World Health Organization (WHO) estimates that there are about 630,000 multi-drug resistant cases of tuberculosis (TB) in the world.
Despite the dire need for new antimicrobials, however, only two new classes of antibiotics have come on the market in the past 30 years, and the development pipeline of anti-Gram-negative antibiotics is at an all-time low. Big Pharma has largely turned its focus away from antimicrobials with their short and unpredictable demand towards more lucrative chronic disorders requiring long-term treatment, such as heart disease and cancer. New antibiotics have proven difficult to design, and even if one were developed today, it would be heavily regulated, need to be used exceptionally carefully, and might become ineffective at any time – an unattractive scenario to most companies.
Cooperation – the name of the game
In an effort to accelerate the delivery of new antibiotics, the Innovative Medicines Initiative (IMI) – a joint undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations – launched the European Gram-negative Antibacterial Engine (ENABLE) in February 2014. The consortium of 18 universities, 10 small and medium-sized companies (SMEs), and four pharmaceutical firms will work together to provide a pipeline of candidate antibiotics against Gram-negative bacteria for testing in the clinic. ENABLE will bring together people who perhaps haven’t worked together before, enabling researchers with potential drug candidates to collaborate with a diverse range of experts in microbiology, pharmacology and chemistry to help advance their molecules through the early drug development process more efficiently than if they were working in isolation.
‘The project is designed to encourage co-operations across the fields of pharmaceutical companies, academic research and SMEs, bringing together a unique set of resources and expertise,’ says Peer Nils Schröder, head of public relations at Basilea Pharmaceutica in Basel, Switzerland, one of the participants.
The six-year, €85m project falls under the IMI’s New Drugs for Bad Bugs (ND4BB) series of programmes. While there are two other ND4BB programmes targeting bottlenecks in pharmaceutical development and effective use of novel antibiotics, ENABLE is more product-oriented. Specifically, the aim here is to identify three antibacterial lead molecules that have promising antimicrobial activity, identify two clinical candidates, and progress at least one compound into Phase 1 clinical trials by 2019. Eight programmes make up the initial ENABLE portfolio, which will be expanded by open calls to create a full development pipeline. R&D work will be reimbursed by IMI at 75%.
For example, MEDINA, an independent non-profit R&D organisation established jointly by the Government of Andalucia (Spain), the University of Granada and Merck Sharp and Dohme de Espana, plans to develop its first novel antibiotics as an ENABLE participant. ‘MEDINA [which discovers new molecules from its natural product libraries] brings to the project one of the novel antibiotic molecules that will be developed within this partnership. Our participation in this programme represents a fantastic opportunity to jointly develop one of the most advanced compounds in our pipeline’, says scientific director, Olga Genilloud.
A win-win scenario
What ENABLE will do is reduce the risks for all those involved. ‘The SME process is de-risked by the fact that skills and resources they don’t have in-house can be applied rapidly to their programme, adding value in the eyes of investors and getting them to a stage where they could attract larger downstream partners or finance to undertake clinical trials,’ explains Claire Skentelbery, secretary general of the European Biotechnology Network in Brussels, Belgium, the ENABLE participant managing the open calls. ‘The pharma process is de-risked by the fact that the early stage innovative products that they would struggle to find and invest in are developed to a mature enough stage that likelihood of failure is much reduced. It is a substantial change in practice for pharma to do this.’
‘The combined approach of having funding and development from Big Pharma – with its knowledge and experience of clinical trials and the regulatory process for drug licensing – coupled with the innovation and expertise of SMEs and academia is likely to have a synergistic relationship,’ says Alan Johnson, head of the department of healthcare-associated infections and antimicrobial resistance at Public Health England in London, UK.
‘We need expertise from Big Pharma and nimble thinking of small companies,’ adds Roslyn Bill, professor of biotechnology at Aston University, UK, an ENABLE participant. ‘Collaboration is the way forward, absolutely – a new way of working is going to make the difference.’
Additionally, ENGAGE partners have signed up to an innovative intellectual property agreement. A key aspect of the agreement is that it allows improvements made to a molecule within the project to be assigned to the original molecule owner on a case-by-case basis. Furthermore, partners that contributed to improvements receive compensation – linked to the budget they used – when any candidate generates revenue, either at the end of the publicly-funded stage or later on after further development.
‘All of us agree that the current model of anti-infective development is failing. This failure is driven by the fact that antibacterial resistance cannot be fully addressed by market forces alone,’ says Vance Fowler, a professor at Duke University’s Bacterial Research Unit, Durham, North Carolina, US. ‘For that reason, public–private partnerships in general, and the ENABLE initiative in particular, are welcome additions to meeting the antibacterial resistance challenge.’
While the cooperative arrangement among ENABLE’s participants is welcomed as a way of generating new antibiotics, beating antibiotic resistance requires a global and multi-pronged approach. As well as setting the right incentives for industry, Basilea’s Schröder says that clear guidelines and well-defined regulatory pathways are very important in bringing forward new drugs.
‘From a basic science perspective, we need a better understanding of mechanism, and better ways to reward compound discovery. We also need a better understanding of the clinical epidemiology that erodes the utility of our existing antibiotics, and better clinical trials to optimise their use,’ says Fowler. ‘We need to address counter-productive antibiotic prescribing practices, and we need to eliminate antibiotics as growth promoting agents in food animal production.’
‘The problem of resistance is of global proportions, so initiatives to tackle resistance ideally need to be undertaken at both national and international levels,’ concludes Johnson.
A global search
Research groups all over the world are trying to find novel ways of thwarting bacteria and overcoming resistance.
Chemists at Technische Universitaet Muenchen in Munich, Germany, have discovered two new ways of permanently inactivating ClpP, an important bacterial protease that is responsible for the pathogenic effects of many kinds of bacteria.
The first approach involves disrupting the arrangement of amino acids required for the cohesion of the protease subunits.
The second acts directly on the core of its active centre, rendering the protein inoperable. Both approaches inhibit the protease in novel ways and are thus very promising for the development of new antibiotics, say the researchers, who discovered a whole series of inhibitors that initiate the two mechanisms. Although the bacteria are not completely disarmed, they produce significantly fewer inflammation-causing toxins, giving the immune system more time to handle the pathogens while the formation of new resistances is suppressed, according to the researchers (JACS, 2014, 136(4), 1360).
Spectinomycin, a natural antibiotic produced by many organisms, does not normally work against tuberculosis (TB). However, using structure-based design, an international team of scientists has generated a new semi-synthetic series of analogues of spectinomycin, which could prove useful for treating drug-resistant TB (Nature Medicine, doi: 10.1038/nm.3458). The drugs increased survival of mice infected with TB and were effective against drug-resistant strains of TB.
This new class of antibiotic works against TB by disrupting the function of the ribosome, the main site for protein synthesis in a cell and, because it binds to a site on ribosomes not shared by other TB drugs, it can be used in combination with other medications. ‘This study demonstrates how classic antibiotics derived from natural products can be redesigned to create semi-synthetic compounds to overcome drug resistance,’ said researcher Richard Lee at St. Jude Children’s Research Hospital, Memphis, Tennessee, US.
Meanwhile, researchers at Rensselaer Polytechnic Institute in Troy, New York, US, are focusing on antimicrobial peptides (AMPs) in the fight against drug-resistant TB. AMPs, which are produced by all organisms, are short strings of amino acids that can break through bacterial cell walls. The researchers, who presented their work at the American Chemical Society meeting in March 2014, have designed and synthesised three novel AMPs, which, in lab tests, could drill into the thick wall of tuberculosis cells and kill Mycobacterium tuberculosis.
The team is now focused on improving their design and understanding exactly how they work. AMPs could overcome drug resistance because bacterial cell membranes have been conserved through a long history of evolution. ‘It’s going to be much more difficult for a bacterium that’s been around for millions of years to reconfigure its membrane,’ said one of the researchers, Georges Belford. ‘That’s the core protective structure that has helped it survive this long.’
Advancing the cause
A team of researchers at the University of Notre Dame, Indiana, US, has hit on a new class of antibiotics to fight drug-resistant bacteria. Using computer modelling and simulation experiments, the researchers discovered that oxadiazoles inhibit penicillin-binding protein 2a of MRSA and the biosynthesis of the cell wall that enables it to resist other drugs. The oxadiazoles, which can be taken orally, have shown promise in treating vancomycin- and linezolid-resistant MRSA in mouse models of infection ((JACS, 2014, 136(9), 3664).
Meanwhile, scientists in the UK have made a key discovery about the intricacies of bacterial communication that could inform efforts to design new anti-infectives that are less likely to cause resistance. According to the researchers, most remedies for infections simply block all the chemical signals – or ‘talk’ – between bacteria. Since bacteria require communication to survive, but this can drastically alter their gene expression, aiding the survival of resistant strains.
This study suggests that more subtle interventions, which only block specific signals that can harm people, may be equally effective at treating infections without leading to resistance (PNAS, doi: 10.1073/pnas.1319175111). ‘We’re only beginning to scratch the surface of the complexity of bacterial social life, and its consequences for disease,’ according to study leader Sam Brown, of the University of Edinburgh’s school of biological sciences in the UK. Brown said that decoding their language opens a new front in the search for mechanisms to control infections.
Emma Dorey is a writer, specialising in life sciences, based in Brighton, UK