RTD info logoMagazine on European Research

N 37 - May 2003
  HEALTH  -  Fighting microbial resistance

Long seen as providing a miracle treatment, antibiotics are beginning to show worrying signs of weakness. A major European research effort is now under way to combat the growing resistance to antibiotic action by infectious agents. In recent years, new molecules, new medical practices and new diagnostic tools have all been developed to try to solve this problem.

A partner in various European research projects, LEO Pharma (DK) has developed many major treatments over the past 90 years. It aims to discover and develop two innovative medicines every decade, knowing that it takes about a decade to develop a pharmaceutical product of this kind.
A partner in various European research projects, LEO Pharma (DK) has developed many major treatments over the past 90 years. It aims to discover and develop two innovative medicines every decade, knowing that it takes about a decade to develop a pharmaceutical product of this kind.
Seventy per cent of the germs responsible for lung disease are today resistant to at least one of the principal molecules available to combat them. Tuberculosis, long regarded as having been marginalised, is now back with a vengeance with deaths running at 1.5 million a year worldwide and the appearance of new multi-resistant strains. Pneumococcus, the agent which causes pneumonia – the world's most deadly infectious disease resulting in 3.5 million deaths a year – is also proving increasingly resistant to current treatment.

Increasing resistance
The problem is widespread and, despite the very wide range of antibiotics available to them, developed countries are far from being risk free. In fact, it is their over-consumption which is one of the main causes of the problem. So-called nosocomial diseases found in a hospital environment regularly make headline news – and 60% of these are caused by resistant microbes. During a recent outbreak in the United Kingdom of infections caused by Staphylococcus aureus, the usually effective methicillin proved ineffective in four out of ten cases. However, bacteria are not the only culprits – the same problem is being encountered in many microbial illnesses, whether viral (such as Aids), fungal, or parasitic (such as malaria).

What is the reason for these mutations? Strangely enough, we still know very little about the exact way in which many common antibiotics work, and thus even less about the precise mechanisms behind the resistance shown by pathogens. The European Molmechmac (Molecular Mechanisms of Macrolides) project has been trying to shed light on these grey areas since December 2000. Researchers are concentrating on the (very widespread) family of macrolide antibiotics in an attempt to improve their understanding of the emergence of resistance and to avoid the problem by modifying the therapeutic molecule.

Genetic transfers
Another problem arises from the fact that when a resistant gene appears, it spreads immediately. 'Given certain conditions, bacteria are able to exchange genetic material, although we do not know exactly how important these flows are, what stimulates them or what reduces them,' explains Anne-Marie Collignon of the Université de Paris-Sud, coordinator of the Artradi project which was launched in September 2002 with the help of European Union funding. 'The digestive tract is a favourable environment for the transfer of resistant genes. It contains several thousand billion bacteria of every kind, concentrated in a restricted space which is ideal for the exchange of genetic material. We chose to focus on in vitro and in vivo studies.'

Staphylococci: these bacteria, first isolated by Louis Pasteur in 1829, are the agents of many infections (boils, septicaemia, etc.).  ©Institut Pasteur
Staphylococci: these bacteria, first isolated by Louis Pasteur in 1829, are the agents of many infections (boils, septicaemia, etc.).

©Institut Pasteur
Many farm animals are also given regular doses of antibiotics, often for long periods, to reduce the risk of infection and to stimulate growth. Their intestinal fauna could therefore also acquire resistant genes and then transmit them to man. 'If we could understand how these transfers occur we may then be able to advise on how to avoid the occurrence of resistance and gain better insight into the exchange of genes in procaryotes,' adds Anne-Marie Collignon.

Uses and abuses
Scientists also want to define a better use of antibiotics. 'There are many ways of reducing the risk of resistance appearing,' explains Anna Lönnroth, scientific manager responsible for microbial resistance at the Research Directorate-General. 'You can combine different molecules and change the combination from time to time, or use certain additives. Common sense also plays a part, for example by only using certain treatment when it is really necessary. Above all, there is the duration of administration and dosage. The worst option is to give low doses over a long period – a sure way of encouraging the emergence of resistance.' 

Serratia marcescens: this bacteria is the source of nosocomial infections which are resistant to many antibiotics. ©Institut Pasteur
Serratia marcescens: this bacteria is the source of nosocomial infections which are resistant to many antibiotics.

©Institut Pasteur
With this in mind, researchers on the Arpac project are analysing and evaluating the practices of many doctors at European hospitals with a view to optimising their methods and harmonising anti-resistance practices. They also want to gather data on the scale of the phenomena in Europe and the pathogens involved.

Developing new antibiotics
Obviously, this growing resistance also brings with it a need for research into new antibiotics. Discovering such molecules is a long, difficult and costly process (about €500 million per molecule) and the market is highly competitive. These difficulties tend to deter pharmaceutical companies – in fact, it has been several years since a new and important antibiotic was launched. The European Union is therefore helping to finance projects aimed at developing antimicrobial agents, some of them in close co-operation with industry. 

Mycoplasma pulmonis: this is the smallest micro-organism living in a free state, without walls, which is also able to multiply inside cells, causing pneumonia in particular. ©Institut Pasteur
Mycoplasma pulmonis: this is the smallest micro-organism living in a free state, without walls, which is also able to multiply inside cells, causing pneumonia in particular.

©Institut Pasteur
The Antistaph project, for example, is exploring the totally new avenue of protease inhibitors. 'Proteases are enzymes directed against the host proteins and which play a key role in the growth and virulence of pathogens,' explains project coordinator Magnus Abrahamson of Lund University. 'Substances which inhibit these proteases have achieved some remarkable successes in the fight against the Aids virus. We now want to draw on these successes to develop antibiotics with a radically different action to that of traditional molecules. A German SME, one of the project partners, aims to patent one or more molecules which prove genuinely effective.' 

The Ribosome inhibitors project is also seeking to develop new antibiotics. Its strategy is to use the mechanisms of protein manufacture as a target for the development of innovative and effective antimicrobial agents. 'We are starting with a molecule, fuscidic acid, the antibiotic effects of which we have long been familiar with,' explains coordinator Frederik Bjorkling of the Danish Foundation Leo Pharmaceutical Products Ltd. 'We want to understand how it works and use this knowledge to find new molecules.' This research is particularly interesting as it is also seeking to develop new agents against mycoses, a field where there is very widespread resistance and where the treatment options are more limited.  

Mycobacterium tuberculosis, or Koch´s bacilli: the tuberculosis agent. ©Institut Pasteur
Mycobacterium tuberculosis, or Koch´s bacilli: the tuberculosis agent.

©Institut Pasteur
'Developing new antibiotics will also benefit recent progress in genomics,' adds    Anna Lönnroth. 'Several microbial genomes have been sequenced recently, increasing the amount of genetic information available and thereby reducing the cost of developing new molecules. This genome revolution will also help us in the key field of diagnostics.'

'Real-time' diagnoses
Diagnostics is a strategic element in the campaign against the over-consumption of antibiotics being observed in the industrialised countries – a practice which is partly to blame for the development of resistance. If doctors had inexpensive and fast – ideally instant – methods for identifying the antibiotics best suited for a given infection, treatment would be improved considerably, in the case of benign and more serious infections. For example, the Dissarm project, coordinated by the National Microelectronics Research Centre (NMRC) in Ireland, is trying to develop a kit able to identify the presence of multi-resistant TB agents from a biological sample. 

Pseudomonas pyocyanea, at the origin of many nosocomial infections (pneumonia, bronchopneumonia, pleurisy, dysentery): not a very pathogenic bacteria, except in individuals with a depressed immune system. ©Institut Pasteur
Pseudomonas pyocyanea, at the origin of many nosocomial infections (pneumonia, bronchopneumonia, pleurisy, dysentery): not a very pathogenic bacteria, except in individuals with a depressed immune system.

©Institut Pasteur
However, research alone is not enough to reduce the incidence of resistance. Radical changes in our social practices are also necessary, and a drastic reduction in our consumption of antibiotics will probably be required. At present, almost 50% of antibiotics are being used either by industry to treat foods against pathogens, or for farm animals, often to promote growth. In human medicine, some 60% of antibiotics are used for complaints of the upper respiratory system, most of which are viral in origin and consequently do not respond to this treatment. A recent study showed that in the United States – and the same probably applies to Europe – half of all antibiotics prescribed by GPs are superfluous and many people are unaware that they are ineffective against viruses.(1 [ http://europa.eu#1 ]) The battle against microbial resistance is therefore far from over. 

(1) 40% of people interviewed in the EU during the last Eurobarometer survey on the attitude of Europeans to science and technology.


  European actions  
  The European Union adopted an initial resolution (Strategies to combat the microbial threat) in 1999, followed by recommendations in November 2002 (For a prudent use of antimicrobial agents in human medicine). 

More than 80 research projects, supported by the Union to the tune of some €100 million, have been carried out over recent years. 

The Genomics and biotechnology for human health priority action under the Sixth Framework Programme is concentrating explicitly on support for networks of excellence and integrated projects engaged in research on new molecules; the mechanisms which explain resistance; the development of alternative treatment and preventive strategies; the development of diagnosis and susceptibility tests; and approaches to epidemiology.

 


  Supporting our neighbours  
  The Armed project (Antibiotic resistance surveillance and control in the Mediterranean region) reflects the Union's desire to take into account the global aspect of the antimicrobial resistance phenomenon. The project was launched on 1 January 2003 for a period of four years, with the aim of extending EU efforts to monitor the problem and disseminate good practices to the south and east of the Mediterranean Basin.

Dr Michael Angelo Borg, of St Luke's Hospital in Malta, is coordinator of the project which includes Northern European institutions (British, Belgian and Dutch) as well as hospitals and universities in Cairo, Tunisia, Ankara, Casablanca, Jordan and Cyprus. The network of experts on antibiotic resistance, which was created as a result of this initiative, will be looking at subjects including antibiotic consumption patterns and practices to control infections, and will also try to identify any cultural factors specific to this region. Similar projects are running in other parts of the world.  

 


  On the viral front  
  We know that viruses do not respond to antibiotics. These formidable pathogens, which are much smaller than bacteria, reproduce by using the replication system of the cells on which they feed. Apart from vaccination, on which research is continuing, there is virtually no treatment to combat them, as is clear from the annual ravages of influenza germs. Nevertheless, a few treatment molecules have, nevertheless, been developed over recent years, most of them against the HIV virus. The first instances of resistance were not long in coming, however, and today nearly 20% of new infections are caused by viruses which are resistant to at least one of the available treatments.

To study this worrying phenomenon, the 16 partners on the European Spread project are collecting data on the spread of HIV resistance. Other projects are trying to understand the appearance of resistance, especially to protease inhibitors. These researchers all share the same goal – to produce new molecules able to eradicate resistant strains of the virus. 

 


  TO FIND OUT MORE  
  http://cordis.europa.eu/
lifescihealth/major
/drugs.htm [ http://cordis.europa.eu/lifescihealth/major/drugs.htm ]
 

 


  CONTACTS  
  Anna Lönnroth, Research DG
email [ mailto:anna.lonnroth@ec.europa.eu ]