New armour against a post-antibiotic era
13 Dec 2012 by Evoluted New Media
As antibiotic resistance rises, there is a real need for new drugs to tackle this very modern problem. David Livermore takes us through the major issues surrounding antibiotic resistance and introduces us to some of the antibiotic research from the Norwich Medical School The recent warning issued by the World Health Organisation that gonorrhoea is becoming resistant to the last drugs in our armoury heightens awareness of the need for new antibiotics, as do the many reports of new hospital ‘superbugs’. There is some excellent primary research on antibiotic discovery - including exciting developments in metagenomics on the Norwich Research Park - but the issue is how to translate this research into marketable treatments.
Selection for bacteria resistant to antibiotics is an inevitable consequence of their use. In some cases, resistance arises by mutation, in others by the exchange of DNA (usually in the form of plasmids) amongst different strains of bacteria. This process of horizontal gene transfer is facilitated in the human or animal gut, which hosts a complex and diverse ecosystem of different bacterial species. What makes the rise of resistance so concerning is the paucity of new treatments being developed and the extent to which big pharma have moved away from the field. Although there is worldwide recognition of the need for new antibiotics, developing them is not currently an attractive business opportunity. Between 1950 and 1960, eight classes of antibiotic were introduced for human use, but in the last 40 years there have been just five. The reasons for this dramatic decline are three-fold.
First, there is the scientific difficulty of finding new agents, which need not only bind to a target but also to reach it across the complex cell wall of Gram-negative bacteria and which can function in different body compartments. By contrast a new heart drug has just one target at one body site.
Secondly, there is the high and frequently-changing regulatory barrier. The purpose of clinical trials is to establish safety and efficacy, but the proofs of efficacy demanded by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are different. The FDA’s requirements, in particular, have undergone repeated change in recent years, complicating clinical trial design. It is now extremely difficult and/or expensive to recruit patients for some indications, including hospital pneumonia. For this reason, drugs tend to be trialled in settings where they are likely to get a licence, rather than where there is a serious clinical need. This is evident with new cephalosporin-ß-lactamase inhibitor combinations, which are being trialled (combined with metronidazole) in intra-abdominal infections rather than in the hospital pneumonias where they are medically needed.
Thirdly, there is the low return on investment. Antibiotics are mostly taken for acute illnesses over short periods of time and are far less profitable than drugs required over a long period of time for chronic illness, such as cancer or neurodegenerative disease. In addition to this, new antibiotics are likely to have their usage restricted, in an attempt to slow down the development and proliferation of resistance.
One concern for the future is the re-emergence of classical diseases that we had thought banished to history, for example tuberculosis. The other worry is that without effective antibiotics, we won’t any longer be able to conduct the many types of modern medicine that lead to immunosuppression. These include therapies for autoimmune disorders and cancer treatments. Many routine surgeries may also become too dangerous to perform owing to the risk of untreatable infection.
The concept of a ‘post-antibiotic era’, where common infections can no longer be successfully treated, has been around since the early ‘90s. At that time, resistance amongst Gram-positive bacteria was rising rapidly. Penicillin-resistant pneumococci were widespread internationally1 and vancomycin-resistant enterococci were also circulating in hospital specialist units2, most extensively in the US. Methicillin-resistant Staphylococcus aureus (MRSA) were relatively uncommon in serious infections at the start of the 1990s, but proliferated to the point, from 2000-3, where they accounted for 40% of all Staphylococcus aureus infections and 10% of all UK bloodstream infections. Similar rises were seen in most of Europe (except the Netherlands and Scandinavia), and in the USA.
The incidence of MRSA infection in the UK and elsewhere has been reduced in recent years, largely via improvements in infection control. Another success is that the incidence of invasive infections due to pneumococci has been reduced by vaccines directed against the pneumococcal serotype where resistance is most prevalent. However, the overall resistance threat has transformed rather than diminished and is compounded by the fact that Western healthcare systems must deal with growing numbers of patients, many of them very elderly, with multiple underlying illnesses that make them highly vulnerable to infection.
The greatest resistance challenges we now face come largely from Gram-negative bacteria. Important opportunistic Gram-negatives in hospitals include Escherichia coli, Klebsiella, Enterobacter, Acinetobacter and Pseudomonas species. Whilst the problem with MRSA was the spread of very few resistant clones among many patients (often carried on the unwashed hands of hospital staff), E. coli infections generally arise from bacteria already present in the body, meaning they are unlikely to be controlled using the same stringent hygiene protocols. Outside of the hospital, but still with Gram-negatives, the World Health Organisation recently highlighted the growing threat posed by multi-drug resistant Neisseria gonorrhoeae. Sulphonamides, penicillins and fluoroquinolones have successively been ‘lost’ to resistance against gonorrhoea and treatment is mostly with the third generation cephalosporins. Although these remain effective in nearly all cases, their margin of activity is being eroded by small progressive reductions in susceptibility and the first few cases of high level resistance are beginning to be reported.3
New approaches are required in our fight against infection, including both new antibiotics and new diagnostics to rapidly identify bacteria and their resistances. One consequence of big pharma’s dwindling interest in antibiotic development is that that the field is now a major opportunity for smaller players. The Norwich Research Park is home to the John Innes Centre and Institute of Food Research, along with the University of East Anglia (UEA), the Norfolk and Norwich University Hospital and The Genome Analysis Centre (TGAC). With this diversity of knowledge and expertise, it is uniquely positioned to support the rapid development of new antibiotics and diagnostics.
Companies emerging from the Norwich BioIncubator - which hosts spin-outs and others attempting to bridge the gap into market exploitation - demonstrate this expertise. These include Procarta Biosystems, which is developing a novel class of DNA-based antibiotics (known as Snare™ antibacterials) that block gene expression by bacteria, preventing them from multiplying or causing disease. A key focus of work on the Park is facilitating the development of narrow-spectrum antibiotics, which only destroy the pathogen causing the infection whilst leaving the host’s intestinal microflora intact. Unlike broad-spectrum antibiotics, the molecular targets for narrow-spectrum drugs only need to exist in a limited number of bacterial species, and this increases significantly the possibilities of finding new classes of antibiotic. Dr Wain, Professor of Medical Microbiology at UEA and his colleague David Williams have set up Discuva, a drug discovery company that has developed a new platform technology. This detects novel potential targets for antibiotics in any species of bacteria and ascertains potential mechanisms of resistance.
The use of narrow spectrum antibiotics should be beneficial, as destruction of the host microflora by broad-spectrum antibiotics often creates the micro-ecology that favours subsequent super-infection. The classic example is Clostridium difficile, which colonises the gut of antibiotic-treated hospital patients and produces toxins leading to symptoms that can range from mild ‘antibiotic-associated’ diarrhoea through to severe necrotising colitis, resolvable only by surgically resecting the gut. Broad-spectrum cephalosporins have proved especially selective for C. difficile and are increasingly avoided in many UK hospitals for this very reason. Narrow-spectrum antibiotics however present special challenges both when it comes to the clinical trials process and for clinical deployment. Patients can only be given narrow-spectrum antibiotics once the organism responsible for infection has been correctly identified. As current diagnostic techniques (by bacteriological culture and susceptibility testing) take around two to three days, patients are likely to already have received several empirical doses of a broad-spectrum antibiotic, precluding their enrolment in a narrow-spectrum trial. Recruiting participants with resistant strains of bacteria is especially hard, because these patients tend to be geographically scattered across non-trial sites.
A collaborative project currently shared between UEA, Norfolk and Norwich University Hospital and TGAC, is investigating the use of next-generation sequencing technology to accelerate the identification of pathogens in blood samples from patients with bacterial infections, removing the need for microbiological culture and the limitations posed by the speed of bacterial growth. This would allow appropriate narrow-spectrum antibiotics to be prescribed within a matter of hours, benefiting patients and facilitating clinical trials of these molecules. Next-generation sequencing may even be able to detect if the organism is resistant to antibiotics and whether the patient’s pathogen belongs to an outbreak strain or not.
Essentially there are three approaches which would make it easier to translate early-stage research into marketable drugs and increase the attractiveness of antibiotic development: (i) increasing the funding for research and development, as is being done under the EU’s Innovative Medicines Initiative (ii) modifying the clinical trial requirements, as in the ‘Limited Population Antibacterial Drug (LPAD) initiative’, currently under discussion in the US and (iii) extending effective patent lives as recently introduced in the US as part of the Generating Antibiotic Incentives Now (GAIN) Act.
Norwich Research Park would like to see Government create an educational, entrepreneurial and regulatory climate that encourages investment and innovation in antibiotic development.
- References
Antimicrobial resistance amongst enterococci isolated in the United Kingdom: a reference laboratory perspective J Antimicrob Chemother 1993; 32: 344-346
Cephalosporin susceptibility among Neisseria gonorrhoeae Isolates — United States, 2000–2010. MMWR Morb Mortal Wkly Rep 2011;60:873-7
- About the author:
- Contacts
Norwich Research Park: Dr Jane Heavens, Projects & Communications Manager, Tel: 01603 274442, email: jane.heavens@norwichresearchpark.com
University of East Anglia Media Relations: Simon Dunford, Media Relations Manager, Tel: +44 (0)1603 592203, email: s.dunford@uea.ac.uk
