Can new discoveries prevent an antibiotic Armageddon?

Antibiotic resistance poses a greater threat to public health than ever before. The Centers for Disease Control and Prevention estimates that about two million Americans fall ill and 23,000 die from antibiotic-resistant bacteria every year, costing the US about US$20bn in direct healthcare costs.

But these figures are likely to rise dramatically in the next few years as resistance to current antibiotics spreads. Because modern healthcare practices – from chemotherapy to surgery – are only made possible by antibiotics, the future of healthcare in general will be greatly affected.

There are promises of new money from non-profit and government funders to support research into antibiotic resistance. President Obama’s recently revealed 2016 budget nearly doubles federal funding for antibiotics to $1.2bn, including $650m to extend existing National Institutes of Health (NIH) and Biomedical Advanced Research and Development Authority (BARDA) programmes of work.

The FDA approved four new antibiotics in 2014, compared with only six antibiotics in the 10 years before that

The Generating Antibiotic Incentives Now Act, set up in 2012 to enable the US Food and Drug Administration (FDA) to fast-track the approval of new antibiotics and extend patent exclusivity, appears to be helping to some degree. The FDA approved four new antibiotics in 2014, compared with only six antibiotics in the 10 years before that. Obama has also set up a task force which is expected to produce a five-year plan in the near future.

A recent UK Government review of antimicrobial resistance (AMR), chaired by Jim O’Neill, has just published its first recommendations.¹ It highlights that current world funding for antibiotic research is still small in comparison with spending on cancer and this needs to be addressed. For example, in the US between 2010 and 2014, some $26bn was spent on cancer research and $14bn on HIV, yet just $1.7bn was spent on AMR.

O’Neill has outlined a series of recommendations aimed at tackling resistance, the first of which is setting up a global AMR innovation fund to boost early research. Details of how this fund would be set up and how it would allocate funds are still to come, but the report suggests that ideas and solutions generated close to where the problems are most acute may be more fertile and tailored to the needs of clinicians and health workers on the front line.

Money is not everything, however; O’Neill’s second recommendation is to make sure that the most is being made of existing drugs, and third, to improve the use of diagnostics wherever they can make a difference. As AMR is failing to attract the researchers needed in academia, and in public and commercial labs, says O’Neill, a fourth recommendation is to train a new generation of scientists in the field. The final recommendation – to track the spread of both infectious diseases and resistance globally – reiterates how important it is to take global action.

O’Neill says: ‘A solution to antimicrobial resistance need not be expensive. It is likely to cost the world much less than 0.1% of global GDP. Weighed against the alternative – US$100 trillion in lost production by 2050 and 10 million lives lost every year – it is clearly one of the wisest investments we could make.’

Figure 1: US National Institutes of Health (NIH) research spending 2010–2014
Source: National Institutes of Health. Figures are in 2010 US dollars

Academic collaboration

Efforts to develop novel antibiotics are said to be hampered by a number of scientific and regulatory hurdles that cannot be tackled easily by any individual organisation acting alone. As a result, academic partners and pharma companies have come together in a new European project to stimulate antibiotic development. Announced in February and called COMBACTE-MAGNET (Combating Bacterial Resistance in Europe – Molecules Against Gram-Negative Infections), the €167m, seven-year project will see innovative studies and activities related to the prevention and treatment of infections caused by multi-drug resistant (MDR) Gram-negative bacteria (GNB).

The collaboration, under the Innovative Medicines Initiative’s AMR research programme New Drugs 4 Bad Bugs, brings together 33 European academic partners and five pharma firms and is to be managed by University Medical Center Utrecht.

Efforts to develop novel antibiotics are said to be hampered by a number of scientific and regulatory hurdles that cannot be tackled easily by any individual organisation acting alone

In particular, the project aims to help prevent respiratory tract infections caused by the GNB Pseudomonas aeruginosa and to develop antibiotics for infections caused by MDR-GNB, including urinary tract and intra-abdominal infections.

Hasan Jafri, COMBACTE-MAGNET Coordinator, and Senior Director, Clinical R&D, Infectious Disease & Vaccines, MedImmune, said: ‘As part of MedImmune’s commitment to bringing novel and effective biologic anti-infectives to patients, collaboration with world-renowned academic partners, such as those involved with COMBACTE-MAGNET, makes the most sense. It is an innovative model for anti-infective development.’

The consortium will also carry out Phase I and II studies with AIC499, a new beta-lactam antibiotic from AiCuris of Germany. It will also collaborate with and strengthen the clinical and lab networks of COMBACTE, the first project within the New Drugs 4 Bad Bugs programme that started in January 2013. In addition, a pan-European collaboration will be created (called EPI-Net) to map and use available surveillance systems in Europe to describe the epidemiology of antibiotic resistance and healthcare associated infections (HCAI).

Big Pharma moves

Some pharma companies are also becoming more active in this field. In December, Merck announced its acquisition of Cubist, a company with two antibiotic compounds in clinical trials. Swiss company Roche has also signed a licensing agreement with Meiji Seika Pharma (Meiji) of Japan and Fedora of Canada to develop a beta-lactamase inhibitor that is currently in Phase I development. Roche has obtained worldwide rights to the product OP0595 from both companies, with the exception of Japan, where Meiji will retain sole rights. The combination of OP0595 with a beta-lactam antibiotic targets severe infections caused by Enterobacteriaceae, including MDR strains.

Smaller companies with promising pipelines include MGB Biopharma, in Scotland, which continues to progress its novel anti-infectives platform. In September 2014, MGB Biopharma secured £4m ($6.4m) from Scottish investors and Innovate UK for further clinical development of its lead antibiotic MGB-BP-3. It has also concluded manufacturing agreements with Almac and Encap for the supply for forthcoming trials with MGB-BP-3 and is on track to start Phase I trials with the oral formulation for treating C.difficile in the first half of 2015; the preclinical IV formulation for hospital-acquired Gram-positive infections is expected to be IND-ready by the end of 2015.

The company says the compound represents a new class of drugs with a new mechanism of action that could transform treatment of common, and potentially fatal, infectious diseases. The MGB-based anti-infective platform, meanwhile, has the potential to deliver drugs against MDR GNB, viruses, fungi and parasites.

Scratching the surface

Another potential antibiotic that has received much attention was discovered by looking at soil organisms. The screening of soil micro-organisms has produced most antibiotics, but only 1% of them will grow in the lab. However, a team of scientists led by Kim Lewis, Director of the Antimicrobial Discovery Center at Northeastern University at Boston, and NovoBiotic Pharmaceuticals, a startup company in Cambridge, Massachusetts, has been working on this problem and has come up with teixobactin – a drug that can treat tuberculosis, septicaemia and C. difficile and which could be available within five years.

It is widely recognised that curbing overuse of antibiotics in healthcare and in food production is necessary

Their approach involved use of the iChip, a miniature device created by Professor Slava Epstein’s team that can isolate single cells and promote their growth in their natural environment, thereby providing researchers with improved access to uncultured bacteria. Novo­Biotic has since assem­bled about 50,000 strains of uncultured bacteria and discovered 25 new antibiotics, of which teixobactin is the latest and most interesting, says Lewis.

Lewis’s lab played a key role in analysing and testing the compound for resistance from pathogens and found it to be the first antibiotic to which resistance by mutations of pathogens have not been identified.² The research team says teixobactin’s discovery presents a promising new opportunity to treat chronic infections caused by Staphylococcus aureus, or MRSA, as well as tuberculosis, which involves a combination of therapies with negative side-effects.

Discovery of new antibiotics is only part of the solution, however. It is widely recognised that curbing overuse of antibiotics in healthcare and in food production is necessary.

The pharma industry, meanwhile, must also manage production issues. Some industry commentators have blamed producers in the developing world for poor waste management systems that have allowed antibiotic pharmaceutical waste streams to be released into the surroundings, enabling resistance to build in the wider environment. During last November’s Antibiotc Week, Karl Rotthier, President of DSM Sinochem Pharmaceuticals urged producers to ‘step up to the plate’ and ensure the cleanest, most rigorous and sustainable methods available are adopted to minimise the environmental impact of and to curb the advance of AMR.

References

1. Review on Antimicrobial Resistance. Tackling a Global Health Crisis: Initial Steps. 2015 http://amr-review.org/sites/default/files/Report-52.15.pdf

2. Kim Lewis, Losee L. Ling, Tanja Schneider, et al. 2015 Nature 517, 455–459 doi:10.1038/nature14098 Published online 07 January 2015