Feature

Superbugs

Efforts to kill superbugs have just made them stronger.

Jack A. Heinemann

When you die, likely it will be because of an infection. Western society does suffer from other afflictions, of course, such as cancer and heart disease, but these have, in a perverse sense, become so important only because antibiotics allow us to live long enough to succumb to them.

Most often those suffering from diseases not caused by microorganisms, such as some cancers, actually die from a secondary infection acquired while in the hospital or from a weakened immune system. Antibiotics have been so successful that most of us believe medicine has found a cure for those nasty germs that so plagued our grandparents and the generations before them. Nonetheless, infectious disease remains humanity's biggest killer.

Antibiotics (or antimicrobial agents in general) have minimised the impact of infectious diseases in the second half of this century. But now the microbes are resistant to every clinically useful drug. Imminent loss of the use of antibiotics is due to the type of drugs we have developed and the way that they are used. We must design very different strategies and agents for the next century. The new therapeutics must do something medical science has never done before -- they must stop disease without inciting resistance amongst our pathogens.

To understand how diseases might be managed we must first understand how the organisms that would cause us all this trouble have come to be. In biology, this is known as the discipline of evolution. Within this discipline, scientists are trying to determine what makes some species cause disease while others are benign. The failure of 50 years of antibiotics to cure disease demonstrates that we have much to learn yet about evolution.

Second, we must discover what was wrong with the drugs we have been using. Third, we must be clever enough as chemists, biochemists, physiologists and geneticists, and responsible enough as clinicians, to develop and administer an entirely different type of therapeutic.

Infectious disease and antibiotic resistance is a problem. At the last transition between centuries, hospitals were places to ease the suffering of the terminally ill or limit the spread of a communicable germ. You died there. The status of hospitals at this end of the century is quite different. You recover there. This could change soon because common, but untreatable, infections caused by microbes -- such as tuberculosis, Streptococcus-pneumonia, and even food poisoning -- are becoming both nastier, that is, more virulent, and resistant to antibiotics.

Hospital-Born Killers

Nosocomial, or hospital-acquired, infections are major killers. In the United States, two to four million people a year contract a nosocomial infection, half involving antibiotic-resistant bacteria. Tens of thousands of them die. Infection by a resistant microorganism prolongs the time of infection while physicians try to determine what antibiotic to apply, increases the potential for the organism to infect other patients and visitors, extends the suffering of the patient and ultimately, makes it just that much more likely the patient will not recover. Up to US$30 billion may be added to heath care costs in the United States by antibiotic resistance.

Resistant microbes are found in every country in the world. In some countries it is estimated that 30% of diarrhoea or pneumonia-causing strains of bacteria are resistant to traditional antibiotics of choice. Many important pathogens are sensitive to only one medically appropriate antibiotic. For example, the enterococci and staphylococci have been controlled until recently by vancomycin. However, resistance to this last drug is increasing rapidly in the United States, from a frequency of 0.8% in 1988 to 4% in 1991 among the enterococci.

This past winter came the widely anticipated but dreaded news that methycillin-resistant Staphylococcus aureus (MRSA) had also acquired resistance to vancomycin. It is now as it was in the beginning, should you be unfortunate enough to contract an infection from these "superbugs".

Disease-causing microorganisms, and their antibiotic-resistant brothers and sisters, are not just found in hospitals. Resistant organisms are becoming common even in environments where antibiotics are not purposefully introduced. This means that even New Zealand must expect resistance problems to grow.

How do the pathogens become virulent? This and other poignant questions are central to discovering the kinds of answers needed for medical advance. As urgent as attention to these questions has become, they must await both a change in approach to drug discovery and a change in attitude to basic scientific research.

Drug discovery has been dominated by a single approach: isolating agents that remove the pathogen from patients with minimal side-effect. At present, such approaches appeal to pharmaceutical companies and governments because they can equate a particular drug with a defined output for the investment. Never mind that just using more of these drugs contributes little to long-term success in managing disease.

Society and government funding agencies have been turning their attention away from funding the kinds of work necessary to develop the new generation of therapeutics. Society is growing fearful of basic science research, and jealous of the monies that fund such work, precisely at the time it needs to again invest in discovery for knowledge's sake.

We have enjoyed 50 years of unprecedented medical success because of the basic research that produced current antibiotics. Future and even better therapeutics and therapeutic strategies could come from small research groups pursuing innovative and basic scientific questions. The perceived dominance of the multi-national pharmaceutical companies or the research agencies of large countries in the area of drug discovery is also a dangerous reliance on old ideas for designing new drugs.

Biologists have no absolute answer to the question of how disease-causing organisms evolve. Nevertheless, basic research (much of it done without pay by those working on weekends in university, government and industrial laboratories all over the world) is providing a solid understanding of how pathogens evolve resistance to antibiotics. These insights are critical to designing resistance-free therapies.

Antibiotic Failure

How have the antibiotics failed? Antibiotics, by definition, are natural products. They are produced by other, usually micro-, organisms. Humans culture the producers and extract and purify the antibiotic for medicinal use.

Resistance is a process of detoxification. Antimicrobial agents are toxins which are toxic particularly to microbes. As such, they are indistinguishable from industrial waste, oil spills, and herbicides and pesticides except that we use some toxins in medicine and others on our lawns.

To microbes that find any of these chemicals toxic, there exists an advantage to being able to detoxify their environment. Rare microbes that can degrade oil or neutralise penicillin, rather than be poisoned by it, grow without competition from those microbes that cannot. The superbug is born when detoxification is coupled to the traits that make microbes virulent.

In nature, we find the genes that detoxify herbicides and mercury deposits tightly attached to the genes that neutralise antibiotics. To microbes, a toxin is a toxin. When you spray your flowers or poop in the woods, you may be contributing to the evolution of antibiotic-resistant pathogens.

The antibiotic producer must be resistant to its own antibiotic. As such, its genes are a valuable commodity for other microbes. Should they acquire the resistance genes, then they too could be resistant. An analysis of the many genes that confer resistance to antibiotics suggests that the origin of resistance among our pathogens is the genes of the producers. This came as a surprise because the producer organisms are different species than the pathogens. Sometimes, producers and pathogens are more different from one another than people are from trees! So how do they share genes?

Genetic Creatures Within

Microbes themselves are infected by what I call the genetic creatures -- viruses and the like -- that carry genes from one organism to the next. Such infective processes have sometimes been thought of as sexual. Thinking of that kind may have produced an unconscious expectation that resistance genes would not be transmitted between microbial species for many of the same reasons that keep human heads on humans and not trees.

We were the first to discover, however, that the genetic creatures in single-celled microbes (descendants of some of the most ancient forms of life on Earth) can also infect creatures very much like you and me! This amazing exchange of genes occurs naturally and probably every form of life is part of the network of gene exchange.

By an interesting quirk of fate, one of the properties that has made modern antimicrobial agents so popular is also the property that succours the evolution of genetic creatures. As I said earlier, antimicrobial agents have been optimised for their ability to clear microbes from patients. In other words, clinically applied drugs inhibit the manifestation of the disease in patients infected by the pathogen.

One way to clinical success is to eradicate the pathogen. Antimicrobial agents prevent the reproduction of pathogens (what microbiologists call "death") and thus act together with the immune system and the other indigenous microorganisms to remove the pathogen from the patient. As good as the drugs are at preventing the reproduction of the pathogen, they are equally good at promoting the reproduction of the genetic creatures.

The success of antibiotics is in part due to their extreme specificity. If they did not affect only certain molecules found exclusively in microbes, then they would be toxic to the patient too. While that makes them clinically acceptable, it may also be their weakness. Antibiotics do inhibit microbial reproduction, but they rarely stop the organism's metabolism. The metabolic activities necessary for acquiring an infection by one of the genetic creatures can persist indefinitely in the "dead" microbe. The dead microbe becomes a vehicle, often immune to the effects of other toxins and natural stresses, that ferries the genetic creatures back into populations of living microbes. In patients or in hospitals, those living microbes can be pathogens.

The puzzle is, why do the gene creatures carry the genes that make microbes resistant to antibiotics? A potential answer to this question is just beginning to form from the research of my group at the University of Canterbury and a handful of investigators from around the world interested in microbial evolution and medicine. The genetic creatures are in their own struggle for survival. Unlike the microbes and you and me, their reproductive rate is mostly determined by how many other genetic creatures occupy the same organism rather than how much food they can get. A genetic creature that carries a resistance gene can kill a genetic creature that does not.

To understand how requires knowing something of the biology of microbes. In contrast to humans, microbes reproduce by asexual division: they divide into two "daughter" cells. When two genetic creatures occupy the same "mother" cell, they force each other into different daughters during cell division. If antibiotics are around, then only the daughter with a resistance gene survives. The other daughter and its genetic creature ultimately disappear from the environment. Antibiotics seem at least as effective at manipulating the interactions of the creatures that infect microbes as they are at manipulating the microbes that infect us.

We became aware of these important aspects of the biology of microbes and gene creatures through basic research on evolution, physiology and genetics. Like most critical observations that lead to technical application, these could not have been anticipated and offered as outputs in grant applications. Basic science research is an investment for a future we cannot predict.

New Ideas Needed

What is the solution to the failure of antibiotics? New ideas. Scientists and clinicians, just like everybody else, must translate their ideas into language. Our relationship to the microbes that cause disease is almost universally characterised as adversarial. No doubt you have heard about the "war" on disease, or microbes, or resistant microbes. Whereas using metaphors like war communicates ideas quickly, they also reveal how we are thinking about the relationship. How we think about the biology of disease determines what we might conceive as remedies.

So far the metaphor has restricted drug discovery to agents that effectively kill microbes, directly or indirectly. The result of that strategy is an impending universal resistance to drugs. As anyone who has ever tried to push a disabled car up hill will understand, if you do not keep it from rolling backwards the car will continue to gain momentum until it rolls right over you. The same is true with life-and-death struggles.

Antibiotics are absolutely lethal to microbes. Our use of these agents forced microbes into an evolutionary T-intersection: they either would become extinct or they would become immune. By not forcing the pathogens into extinction with antibiotics, they now have a momentum that makes all new lethal agents even less likely to last even as long as the old agents.

New strategies are beginning to emerge. Probiotics, or the use of other microbes to control the spread of pathogens (long advocated by those who practice "alternative" medicine) is attracting renewed attention. But do not be fooled: when probiotics, herbal remedies or other so-called natural cures create conditions lethal to pathogens, then these strategies may be just more of the same. Attempts to design agents that convert pathogens into benign co-inhabitants rather than kill the pathogen ought to be encouraged.

The strategy with the greatest potential, however, is research, governed by a humble recognition of how much we don't know and guided by a confidence in our capacity to learn.

Jack A. Heinemann is with the Department of Plant and Microbial Sciences at the University of Canterbury.