The news hit the headlines last Summer: hospital patients in India and Pakistan brought to Europe a bacterium which resists every contemporary antibiotic. A number of them died, whilst the others had a narrow escape. Of course this is not the first ‘multi-resistant’ bacteria: official statistics show that in Europe over 150,000 people die each year from an infection they have picked up in a hospital. But the NDM-1 bacterium, or New Delhi Metallo-bata-lactamase, is particularly alarming for the specialists, as not only is it intrinsically dangerous but it can in addition transmit its antibiotic resistance capacity to other types of bacteria.

The New Delhi bacterium first made waves in 2009, when a Swedish citizen of Indian origin was admitted to a hospital in the Indian capital for a simple abscess. Despite the healthcare he received his condition worsened and he was thus urgently sent back to Sweden. A bacterium which was apparently resistant to every antibiotic was eating away at him from the inside. In the end the Swedish doctors found a way to overcome it. But the affair made a big splash, above all after an alarmist article published in the much respected The Lancet Infectious Diseases. A study has shown that the Indian bacterium (New Delhi Metallo-Beta-Lactamase-1 or NDM-1) has been imported into several European countries, notably Great Britain, but also France, Australia and even Belgium: a Belgian patient of Pakistani origin died because of an infection picked up on a journey to Pakistan. He was the victim of a car accident and was hospitalised with a serious wound to his leg. Thanks to his diabetes, his injury healed badly, offering an entry point to bacteria. NDM-1 rushed in to take advantage. The man was taken back to Belgium where doctors at the VUB hospital centre attempted to treat him with the latest antibiotics. But to no avail. They tried an older medicine, colistine, but with no greater success, and the patient finally succumbed to his infection.

The specialists are worried because the New Dehli bacterium owns a formidable weapon. ‘It manufactures an enzyme, called metallo-beta-lactamase, capable of destroying the antibiotics which belong to three great existing families: penicillins, cephalosporines and carbapenems,’ explains Professor Jean-Marie Frère (Centre for Protein Engineering at the ULg). ‘In addition, the bacterium possesses several copies of this gene, which facilitates the transfer of this gene to other bacteria, either of the same species or a different species.’ The exchange of genetic material between two bacteria can take place through direct contact: the transfer of a piece of chromosome or of a plasmide. A piece of DNA can also be transported from one bacteria to another by a bacterial virus (a phage) but this mechanism involves the death of the ‘donor’ bacteria. It is a very common mechanism: it is for example thought that bacteria frenetically exchange DNA within our intestines. A harmless bacterium can thus pass on its resistance capabilities to a pathogenic. We might thus suspect the dissemination of this antibiotic resistant gene to other bacteria which are dangerous to human beings to a greater or lesser extent. At the point researchers have discovered a gene coding for β-lactamase NDM-1 in at least two bacterial species: Escherichia Coli and Klebsiellae pneumoniae. The former is a bacterium found in our digestive systems, but of which certain strains can prove to be pathogenic, and even fatal in certain cases.

An alarm bell in the Southern hemisphere

The exotic origins of the bacteria, in India and Pakistan, are not in themselves cause for concern. ‘There are resistant bacteria all over the planet,’ explains Jean-Marie Frère. ‘And unfortunately, like any microbe, when an infected person takes a plane the bacteria can go round the world in a few hours.’ The fact remains that a growing number of specialists have been sounding the alarm bell concerning the unbridled use of antibiotics in a certain number of countries in the Southern hemisphere, in particular in the Indian sub-continent and in Africa. The problem is a double one. First of all the hospital hygiene rules in poor countries are less rigorous, and thus the risk of contracting an infection is increased. Secondly the less controlled use of antibiotics encourages the appearance of resistant bacteria. In certain countries antibiotics are sold freely. Badly informed or poorly monitored medically, patients often stop their treatment prematurely, when the illnesses symptoms disappear, not knowing that they have in this way perhaps spared the most resistant bacteria. Without any competitors in the human body – as all the others have been killed by the bacteria – these strains can thus proliferate at the slightest opportunity. Finally, certain countries in the South are victims of a parallel market in fake medicines, for example antibiotics which have been diluted by 50 to 80%, which causes exactly the same problem as prematurely ending treatment: selecting within the patient’s body the most different strains. ‘Today,’ explains Jean-Marie Frère, ‘the seriousness of resistance to antibiotics is more or less a North-South gradient.’

Concerning the NDM-1 bacterium, Professor Patrice Nordmann, the director of an INSERM (French National  Insitute of Health and Medical Reserach) research unit which studies bacteria, considers ‘that there is  no need to boycott journeys to India or Pakistan,’ but that on the other hand ‘is is better to avoid being admitted to hospital’ (interview published in Le Point magazine on 13/08/2010). The message is not so much aimed at people who are hospitalised in an emergency but more at a growing number of Europeans and Americans who practice medical tourism in countries where health care or surgery is much cheaper than it is here. Indian clinics for example attract Western patients with cosmetic surgery fees which cannot be beaten by the rest of the competition. The problem is not for all that restricted to India or Pakistan: patients admitted to hospitals in Turkey, Greece or the Maghreb countries regularly return home with infections which resist antibiotics.

Towards new treatments?

If current antibiotics seem powerless against the New Dehli bacteria, can we in the short term hope for a new medicine which would overcome this dangerous microbe? Unfortunately not. ‘The research into new antibiotics is as good as dead in the water,’ bemoans Professor J.M. Frère. ‘We have known about the problem of metallo-beta-lactamases for twenty years or so. In 1993 the Centre for Protein Engineering began a study of this domain. At the time public financing was available, as well as money from the pharmaceutical industry. Unfortunately our work, as well as that of others, showed that we will doubtless be unable to develop a broad spectrum medicine against metallo-beta-lactamases, but that we would need several different molecules, adapted to each family or sub-family. In short it would be expensive to develop for a market which would each time be relatively limited. Today funding for this type of research has practically disappeared. The pharmaceutical industry prefers to invest in chronic disease. The patients have to take treatments for life; that brings in a lot more.’

It is the whole battle against antibiotic resistant bacteria which is at stake. The experts, it is true, cannot agree amongst themselves. A certain number consider that it is necessary to pull out all the stops, in terms of means, on policies aiming at preventing the appearance and spreading of resistant strains, essentially by limiting the use of antibiotics. The people who argue for this strategy hold that the frantic race between the pharmaceutical industry and bacteria is doomed to failure in the sense that each new antibiotic, by exercising selection pressure on the one or more targeted bacteria, inevitably encourages the appearance of resistant strains. Did not the first bacteria resistant to penicillin arrive at the end of the 1940s, in other words hardly a few years after the use of the first antibiotic was begun? More recently, bacteria in possession of a genetic heritage capable of manufacturing metallo-beta-lactamases, such as NDM-1, have appeared several years after the launching of a new family of antibiotics: the carbapenems. The bacteria, in other words, always find a way to get around the attack. It is only a question of time.

Researchers have already detected over 800 enzymes capable of destroying antibiotics! The bacteria owe this genetic diversity to their very rapid reproduction: one cell division every twenty minutes! If the original bacterium finds something on which to feed its descendants would reach the mass of the Earth in less than 72 hours! This is certainly a little theoretical, but there exists the non negligible probability of random genetic mutation during each reproduction. It is thus highly likely that a resistant gene could adapt to new antibiotics in these conditions. Environment selection takes care of the rest. In effect, in a certain number of cases bacteria already possess this resistant gene in their make-up, but do not necessarily express it. That is explained by the fact that the majority of antibiotics are derivatives of natural molecules. Penicillin, for example, comes from a fungus. In nature certain bacteria are already often in contact with molecules which closely resemble antibiotics; they have thus already learned how to defend themselves against them. ‘Horizontal’ transmission between strains or species thus contributes to the spreading of resistance in the bacteria world. It would thus be ideal to find an entirely synthetic antibiotic. ‘That would doubtless give us at least ten years start on the bacterial response,’ estimates Jean-Marie Frère.

But whilst we are waiting for this hypothetical super-antibiotic it is necessary, according to Jean-Marie Frère, to carry on with research, ‘in order to stay a step ahead,’ as other bacteria of the same type as NDM-1 will inevitably emerge in the years to come. The CIP has not worked on the New Dehli bacterium in particular, but instead on bacteria which produce very similar beta-lactamases and which confer the same type of resistance to several forms of bacteria, including E.coli and Klebsiella (1). In 2008, Jean-Marie Frère and several other specialists published in The Lancet an impassioned plea in favour of research into antibiotics (Read: Antibiotics against Bacteria). But two years later they do not feel that they have been listened to.

Clément Violet

(1) Recent work by the University of Liège’s Centre for Protein Engineering on Metallo-β-lactamases.

Useful readings :

• Gerard D. Wright, Q&A: Antibiotic resistance: where does it come from and what can we do about it?,  BMC Biology 2010, 8:123 Read the article

• Antibiotics against bacteria Read the article