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European Biopharmaceutical Review

One Bug, One Drug

In order to develop effective antibiotics, researchers must investigate changes in the composition of bacteria in the body over time. However, current microbiology methods have only revealed a fraction of the species that are present, making advances in this area difficult

There has been a dramatic decline in the development of new antibiotics. Between 1950 and 1960, eight classes of antibiotics were introduced for human use whereas, in the last 40 years, there have only been five. When coupled with the rising threat of antibiotic resistance, this leads many to believe that we are fast approaching a ‘post-antibiotic era’, where common infections can no longer be treated and may even prove fatal.

Growing Concern

The current crisis started to become apparent in the late 1990s, when resistance among grampositive bacteria was rising rapidly. Penicillin-resistant pneumococci were widespread internationally and vancomycin-resistant enterococci were also circulating in hospital specialist units most extensively in the US (1,2).

At the start of 1990, methicillin-resistant Staphylococcus aureus (MRSA) were still relatively uncommon, at least in serious infections in the UK. However, between 2000 and 2003, resistance had proliferated to the point where they accounted for 40 per cent of all Staphylococcus aureus bacteraemias, and 10 per cent of all bacteraemias in the UK excluding Scotland. Similar increases were seen in most of Europe (except The Netherlands and Scandinavia) and in the US.

Although MRSA has been brought under control by improved infection control measures, resistance has increased in a wide array of gramnegative pathogens, including those with extended-spectrum betalactamases, quinolone resistance and carbapenemases – which inactivate what were previously the most universally active antibiotic class, carbapenems.

A growing concern is that without effective antibiotics, we will be unable to conduct many types of modern medicine, such as therapies for autoimmune disorders and cancer treatments that lead to immunosuppression. Additionally, the risk of untreatable infection will make many routine surgical procedures too dangerous to perform. Studies being conducted at Norwich Research Park are directed at addressing this situation through antibiotic discovery, as well as by lowering the barriers that prevent the translation of drug discovery into marketable treatments and by improving the precise diagnosis of infectious disease.

Obstacles to Development

Even when new antibiotics are identified via drug discovery, there are still several phases of clinical trials to go through before a drug can be brought to market. These include stages to establish pharmcokinetic behaviour (blood levels and tissue distribution), safety and efficacy, and performance in comparison with current standard of- care drugs. Although there is worldwide recognition of the need for new antibiotics, developing them is not currently an attractive business opportunity for Big Pharma. Companies such as Roche, Pfizer, Bristol Myers Squibb and Eli Lilly have all moved away from the field. The reasons for the dramatic decline in antibiotic development are three-fold.

First, there is the difficulty of finding new agents which need to not only bind to the target but reach it across the complex cell wall of gram-negative bacteria. The agent must also function accordingly in different body parts. (In contrast, a new heart drug only has one target in the body.)

Second is the low return on investment. Antibiotics are mostly taken for acute illnesses over a short space of time, and are far less profi table than drugs required over longer periods for chronic illness, such as cancer or neurodegenerative diseases. In addition, new antibiotics are likely to have their usage restricted in an attempt to slow down the development and proliferation of resistant strains of bacteria.

The third reason 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 Food and Drug Administration (FDA) and the European Medicines Agency vary. The FDA’s requirements, in particular, have changed repeatedly; it is now extremely difficult and sometimes expensive to recruit patients for some indications. 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.

Narrow Spectrum Antibiotics

One consequence of Big Pharma’s dwindling interest in antibiotic development is that the field is now a major opportunity for smaller microbiology players. Indeed, exciting technology emerging from labs is opening up the possibility for narrow spectrum, targeted antibiotics, which have many advantages.

All antibiotics exert a Darwinian selection on bacteria, favouring those that are resistant, changing the healthy bacterial flora and encouraging the emergence of ‘superbugs’. Broad spectrum antibiotics – compared to narrow spectrum ones – have a devastating effect on the gut flora, which contains more bacterial cells than the body contains human cells, some of them with the potential to act as future opportunistic pathogens. In some cases, resistance arises by mutation, in others it occurs through the exchange of DNA (usually in the form of plasmids) among different strains of bacteria. Horizontal gene transfer is facilitated in the human or animal gut, with its complex and diverse ecosystem of different bacterial species.

It is now important to develop narrowspectrum antibiotics which destroy just the pathogen – for example, Clostridium difficile – thereby curing the infection while leaving the host’s intestinal microflora intact. The search for new targets is directed at mechanisms that either act on fundamental processes within the organism so that it cannot replicate, or that weaken it sufficiently to ensure that competitive pressure within the gut reduces its virulence.

One advantage of narrow-spectrum drugs is that the molecular target for each drug only needs to exist in a limited number of bacterial species, and this significantly increases the possibilities of finding new classes of antibiotic for each bacterial pathogen.

A new platform technology called SATIN (Selective Antibiotic Target IdentificatioN) detects more targets for antibiotics in any species of bacteria and ascertains potential mechanisms of resistance. This platform has been used to identify multiple, chemicallytractable small molecules with activity against Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii, representing a wide range of gram-negative pathogens.

Improved Diagnostics

Narrow-spectrum antibiotics, however, present special challenges when it comes to the clinical trials process and finding a market in clinical medicine. Recruiting participants with resistant strains of bacteria is problematic as these patients tend to be scattered geographically across non-trial sites. More critically, as the clinical researcher will not know what bacteria are causing the infection until the lab results arrive two days after clinical diagnosis, it is necessary – at least in severe, lifethreatening infection – to begin with broad spectrum antibiotics. Once these have been given, however, the patient then becomes ineligible for enrolment into a trial for any other antibiotic for that infection.

To overcome this challenge, researchers are working to improve techniques for early diagnosis in order to identify the specific strains of bacteria that are implicated. This will facilitate recruitment of patients to trials for narrow-spectrum antibiotics, identifying those with pathogens that are likely to be susceptible.

One collaborative project is investigating the use of next-generation sequencing technology – which resembles a molecular version of the agar plate for bacteria and electron microscopy for viruses – to accelerate the identification of pathogens in blood samples from patients with bacterial infections. Using nucleic acid removes the need for microbiological culture and speeds up the microbiological diagnosis. Aside from facilitating clinical trails, rapid and accurate diagnosis would allow appropriate narrow-spectrum antibiotics to be prescribed within a matter of hours, benefiting patients and improving antibiotic stewardship. Next-generation sequencing may even be able to detect whether the patient’s pathogen belongs to an outbreak strain or not, and if the organism is resistant to antibiotics.

Encouraging Antibiotic Development

We would like to see the UK Government create an educational, entrepreneurial and regulatory climate that encourages investment and innovation in antibiotic development, with the following measures:

● Increasing the funding for research and development, as is being done under the EU’s Innovative Medicines Initiative

● Modifying the clinical trial requirements, as in the Limited Population Antibacterial Drug (LPAD) initiative, currently under discussion in the US

● Extending effective patient lives, as recently introduced in the US as part of the Generating Antibiotic Incentives Now (GAIN) Act

These three approaches would make it easier to translate earlystage research into marketable drugs and increase the attractiveness of antibiotic development. Also, this would enable highly specific, narrowspectrum antibiotics to be designed, benefiting both patients and societal management of infections.

References

1. Munoz R, Musser JM, Crain M et al, Geographic distribution of penicillin-resistant clones of Streptococcus pneumoniae: characterisation by penicillinbinding protein profile, surface protein A typing, and multilocus enzyme analysis, Clin Infect Dis 15: pp112-118, 1992

2. Woodford N, Morrison D, Johnson AP and George RC, Antimicrobial resistance amongst enterococci isolated in the United Kingdom: a reference laboratory perspective. J Antimicrob Chemother 32: pp344-346, 1993


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David Livermore is Professor of Medical Microbiology at Norwich Medical School, University of East Anglia, Norwich Research Park, UK. This follows 14 years of being a Director of the Antibiotic Resistance Monitoring and Reference Laboratory at the Health Protection Agency. David still acts as the Lead on Antibiotic Resistance at HPA.

John Wain is Professor of Medical Microbiology at the University of East Anglia, Norwich Research Park, and Chief Scientific Officer for Discuva Ltd. He was previously the Director of the Laboratory for Gastrointestinal Pathogens at the HPA. He still acts as the HPA’s Lead on Gastrointestinal Infection.
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