SCIENCE / Back to a plague-ridden future: As viruses mutate to beat modern drugs, new epidemics of old illnesses threaten. Sharon Kingman investigates

DISEASES that were once thought to have been largely conquered are coming back to plague us. Tuberculosis, malaria and gonorrhoea head the list of infectious illnesses that are fighting a rear-guard action against modern drugs: they are mutating rapidly to produce resistant strains at a faster rate than we can invent new drugs. The result is that we now have worldwide epidemics of illnesses that should have been consigned to history.

The most startling example is tuberculosis, which had almost been eradicated by the widespread use of antibiotics and vaccines after the Second World War. But in 1990 and 1991 the United States reported 13 outbreaks of tuberculosis caused by a strain of bacteria that was resistant to two or more of the most powerful anti-TB drugs. This came as a great shock to American doctors. A few years earlier, in 1985, they had even stopped monitoring strains of the TB bacteria for drug resistance. The decision, says Dr Dixie Snider, former director of the tuberculosis division at the United States Centers for Disease Control, in Atlanta, 'was taken partly to save money and partly because resistance seemed to be declining'.

Drug resistance, however, was far from being in decline. In 1991, medical scientists in New York State found that 13 per cent of tuberculosis bacteria they analysed could survive attack with the two most effective anti-TB drugs - isoniazid and rifampicin. The problem for people infected with these strains of tuberculosis is the paucity of other treatments open to them, says Dr Mario Raviglione, a tuberculosis researcher at the World Health Organisation in Geneva. 'When you are infected with organisms that are resistant to isoniazid and rifampicin, the two most powerful agents, then you are in trouble because you are left with drugs that are relatively weak,' he says. 'If the bacteria are resistant to all the drugs we have available, the disease becomes practically incurable. It becomes the disease it was at the beginning of the century.'

The example of tuberculosis demonstrates how and why drug resistance develops. Treatment for tuberculosis takes many months, sometimes up to a year. This is because many of the bacteria lie dormant in the body; a long-term course of treatment ensures that the drugs are present in the body to strike the bacteria when they become active.

This is all very well if the patient remembers to take the drug regularly. The trouble is, tuberculosis often strikes in communities of poor and uneducated people who do not realise the importance of continuing a course of drugs over a long period of time. In one study of tuberculosis patients in New York's Harlem, nine out of 10 people failed to complete their treatment, often stopping the drugs as soon an they felt better, after just three to four weeks,

What happened here is that those TB bacteria that had survived the initial treatment had done so because they were slightly more resistant to the drug. Within two to three months, the patient relapsed, felt ill and started on a new course of treatment. Again, the bacteria which were most susceptible died immediately, while those which were more resistant survived. Eventually the only bacteria left were those completely unaffected by the antibiotic. And because treatment involved many drugs, the resulting strains of the tuberculosis bacterium proved to be resistant to several drugs - sometimes as many as seven.

Micro-organisms - bacteria and viruses - can become drug resistant in different ways. In the case of isoniazid-resistant tuberculosis, mutations have caused the bacterium to lose an enzyme called peroxidase. Dr Douglas Young, a Medical Research Council scientist who works at the Royal Postgraduate Medical School at Hammersmith Hospital, London, says it is thought that the enzyme activates the drug. (Putting the gene for the enzyme back into the resistant bacteria makes them susceptible to the drug again.)

Young predicts that this discovery will make it possible to find out much more quickly if someone is infected with a drug-resistant strain of tuberculosis - by looking for the genetic mutation rather than growing bacteria laboriously to see if they can survive in the presence of the drug. At present, it can take up to 12 weeks to find out this information. By the time the doctor knows which drugs to prescribe, the patient may be dead.

Whereas drug-resistant TB loses an enzyme, drug-resistant gonorrhoea gains one. Mutations in the gonorrhoea bacterium that cause production of penicillinase - an enzyme that destroys the antibiotic penicillin - have been responsible for the establishment of virulent strains of the sexually-transmitted disease in many developing countries.

Dr Anthony Jephcott, director of the Public Health Laboratory Service's National Gonococcus Reference Unit in Bristol, says resistance often arises in those countries where control of antibiotics is poor: the drugs are sold over the counter, without a prescription, often as single tablets. 'Prostitutes particularly will take a very low dose of penicillin almost permanently, to protect themselves.' If they took a high dose all the time, he says, they would probably kill all the strains that they met; but taking a low dose fails to wipe out those bacteria that are just a bit resistant, and encourages them to grow.

In the case of penicillin-resistant gonococci (or any other infection with antibiotic-resistant bacteria), doctors can prescribe other antibiotics that will be effective. But this option may not be available to patients in developing countries, because alternative antibiotics are often much more expensive. Only about 1 or 2 per cent of gonococci isolated in the UK are resistant to penicillin and they are usually imported cases, Jephcott says.

In the case of malaria, too, the World Health Organisation says resistance has been encouraged because many patients cannot afford to take complete courses of drugs that will eradicate the parasite. The rise of resistance was slow but steady. Chloroquine, discovered during the Second World War, used to be effective against all types of malaria. Then, in the 1950s, resistance began to appear in South East Asia and, separately, in South America. Chloroquine-resistant malaria is now spreading across Africa.

Some of the anti-malarial drugs inhibit an enzyme, called dihydrofolate reductase, which is essential to the survival of the malaria parasite. But resistant strains of the parasite have mutated their enzyme so that the drugs no longer block its action. Other research has suggested that resistance is due to the ability of the malarial parasite to 'pump' the drugs out of its cells. Several strains of malaria have now become resistant to newer drugs. In some countries, treatment with Fansidar, a combination of pyrimethamine and sulfadoxine, or with mefloquine, is no longer effective. Some people in Thailand have even become infected with malaria that is resistant to all therapies.

Drug resistance is not unique to the centuries-old diseases such as malaria and tuberculosis; it has also hampered the fight against Aids. Scientists have recently become aware of the ways that human immunodeficiency virus becomes resistant to the drug AZT, the most widely used treatment. AZT works by blocking a vital enzyme in the virus but it appears that HIV, which can mutate far more rapidly than tuberculosis, malaria or gonorrhea, generates 'escape mutants' in a patient undergoing treatment. The multiplication of these mutants in the body eventually renders AZT ineffective.

Earlier this month, scientists proposed a strategy for fighting this ability of HIV to develop resistance. They suggested using a cocktail of several drugs at once to force the virus into a corner; the mutations it needs to survive the chemical onslaught are so profound that it makes the virus incapable of replication. Douglas Richman, a virologist at the University of California, San Diego, likens the strategy to a game of chess with the drug cocktail forcing HIV 'to make a fatal combination of mutations'.

So far, however, such a multi-drug approach to Aids has not gone beyond test-tube experiments. The toxic side-effects on Aids patients are a considerable barrier to success. But ultimately the ability of medical science to fight resistance in Aids or other diseases comes down to the speed with which we can develop new and safe drugs.

Barry Bloom, of the Howard Hughes Medical Institute and Albert Einstein College of Medicine, wrote in Nature last year that the outbreak of drug-resistant tuberculosis 'reminds us that there is a constant threat from mutations of infectious pathogens'. Without an effort to control the drugs we have, and more support for development of new drugs and vaccines, he said, 'we may be working our way back to a frightening future'.-

(Photograph omitted)