In the pump-factories of the inner cell membrane, new pumps have evolved that specifically latch on to antibiotics and spew them back out of the cell before they can kill. Other bacteria have mutated their interior protein factories so that the assembly-line no longer offers any sabotage-sites for site-specific protein-busting antibiotics. Yet another strategy is to build excess production capacity, so that instead of two or three assembly lines for protein, a mutant cell will have ten or fifty, requiring ten or fifty times as much drug for the same effect. Other bacteria have come up with immunity proteins that will lock-on to antibiotics and make them useless inert lumps.
Sometimes — rarely — a cell will come up with a useful mutation entirely on its own. The theorists of forty years ago were right when they thought that defensive mutations would be uncommon. But spontaneous mutation is not the core of the resistance at all. Far more often, a bacterium is simply let in on the secret through the exchange of genetic data.
Beta-lactam is produced in nature by certain molds and fungi; it was not invented from scratch by humans, but discovered in a petri dish. Beta-lactam is old, and it would seem likely that beta-lactamases are also very old.
Bacteriologists have studied only a few percent of the many microbes in nature. Even those bacteria that have been studied are by no means well understood. Antibiotic resistance genes may well be present in any number of different species, waiting only for selection pressure to manifest themselves and spread through the gene-pool.
If penicillin is sprayed across the biosphere, then mass death of bacteria will result. But any bug that is resistant to penicillin will swiftly multiply by millions of times, thriving enormously in the power-vacuum caused by the slaughter. The genes that gave the lucky winner its resistance will also increase by millions of times, becoming far more generally available. And there’s worse: because often the resistance is carried by plasmids, and one single bacterium can contain as many as a thousand plasmids, and produce them and spread them at will.
That genetic knowledge, once spread, will likely stay around a while. Bacteria don’t die of old age. Bacteria aren’t mortal in the sense that we understand mortality. Unless they are killed, bacteria just keep splitting and doubling. The same bacterial “individual” can spew copies of itself every twenty minutes, basically forever. After billions of generations, and trillions of variants, there are still likely to be a few random oldtimers around identical to ancestors from some much earlier epoch. Furthermore, spores of bacteria can remain dormant for centuries, then sprout in seconds and carry on as if nothing had happened. This gives the bacterial gene-pool — better described as an entire gene-ocean — an enormous depth and range. It’s as if Eohippus could suddenly show up at the Kentucky Derby — and win.
It seems likely that many of the mechanisms of bacterial resistance were borrowed or kidnapped from bacteria that themselves produce antibiotics. The genus Streptomyces, which are filamentous, Gram-positive bacteria, are ubiquitous in the soil; in fact the characteristic “earthy” smell of fresh soil comes from Streptomyces’ metabolic products. And Streptomyces bacteria produce a host of antibiotics, including streptomycin, tetracycline, neomycin, chloramphenicol, and erythromycin.
Human beings have been using streptomycin’s antibiotic poisons against tuberculosis, gonorrhea, rickettsia, chlamydia, and candida yeast infection, with marked success. But in doing so, we have turned a small-scale natural process into a massive industrial one.
Streptomyces already has the secret of surviving its own poisons. So, presumably, do at least some of streptomyces’s neighbors. If the poison is suddenly broadcast everywhere, through every niche in the biosphere, then word of how to survive it will also get around.
And when the gospel of resistance gets around, it doesn’t come just one chapter at a time. Scarily, it tends to come in entire libraries. A resistance plasmid (familiarly known to researchers as “R-plasmids,” because they’ve become so common) doesn’t have to specialize in just one antibiotic. There’s plenty of room inside a ring of plasmid DNA for handy info on a lot of different products and processes. Moving data on and off the plasmid is not particularly difficult. Bacterial scissors-and-zippers units known as “transposons” can knit plasmid DNA right into the central cell DNA — or they can transpose new knowledge onto a plasmid. These segments of loose DNA are aptly known as “cassettes.”
So when a bacterium is under assault by an antibiotic, and it acquires a resistance plasmid from who-knows where, it can suddenly find an entire arsenal of cassettes in its possession. Not just resistance to the one antibiotic that provoked the response, but a whole Bible of resistance to all the antibiotics lately seen in the local microworld.
Even more unsettling news has turned up in a lab report in the Journal of Bacteriology from 1993. Tetracycline-resistant strains in the bacterium Bacteroides have developed a kind of tetracycline reflex. Whenever tetracycline appears in the neighborhood, a Bacteroides transposon goes into overdrive, manufacturing R-plasmids at a frantic rate and then passing them to other bacteria in an orgy of sexual encounters a hundred times more frequent than normal. In other words, tetracycline itself now directly causes the organized transfer of resistance to tetracycline. As Canadian microbiologist Julian Davies commented in Science magazine (15 April 1994), “The extent and biochemical nature of this phenomenon is not well understood. A number of different antibiotics have been shown to promote plasmid transfer between different bacteria, and it might even be considered that some antibiotics are bacterial pheromones.”
If this is the case, then our most potent chemical weapons have been changed by our lethal enemies into sexual aphrodisiacs.
The greatest battlegrounds of antibiotic warfare today are hospitals. The human race is no longer winning. Increasingly, to enter a hospital can make people sick. This is known as “nosocomial infection,” from the Latin for hospital. About five percent of patients who enter hospitals nowadays pick up an infection from inside the hospital itself.
An epidemic of acquired immune deficiency has come at a particularly bad time, since patients without natural immunity are forced to rely heavily on megadosages of antibiotics. These patients come to serve as reservoirs for various highly resistant infections. So do patients whose immune systems have been artificially repressed for organ transplantion. The patients are just one aspect of the problem, though; healthy doctors and nurses show no symptoms, but they can carry strains of hospital superbug from bed to bed on their hands, deep in the pores of their skin, and in their nasal passages. Superbugs show up in food, fruit juices, bedsheets, even in bottles and buckets of antiseptics.
The advent of antibiotics made elaborate surgical procedures safe and cheap; but nowadays half of nosocomial infections are either surgical infections, or urinary tract infections from contaminated catheters. Bacteria are attacking us where we are weakest and most vulnerable, and where their own populations are the toughest and most battle-hardened. From hospitals, resistant superbugs travel to old-age homes and day-care centers, predating on the old and the very young.
Staphylococcus aureus, a common hospital superbug which causes boils and ear infections, is now present in super-strains highly resistant to every known antibiotic except vancomycin. Enterococcus is resistant to vancomycin, and it has been known to swap genes with staphylococcus. If staphylococcus gets hold of this resistance information, then staph could become the first bacterial superhero of the post-antibiotic era, and human physicians of the twenty-first century would be every bit as helpless before it as were physicians of the 19th. In the 19th century physicians dealt with septic infection by cutting away the diseased flesh and hoping for the best.
Staphylococcus often lurks harmlessly in the nose and throat. Staphylococcus epidermis, a species which lives naturally on human skin, rarely causes any harm, but it too must battle for its life when confronted with antibiotics. This harmless species may serve as a reservoir of DNA data for the bacterial resistance of other, truly leth
al bacteria. Certain species of staph cause boils, others impetigo. Staph attacking a weakened immune system can kill, attacking the lungs (pneumonia) and brain (meningitis). Staph is thought to cause toxic shock syndrome in women, and toxic shock in post-surgical patients.
A 1994 outbreak of an especially virulent strain of the common bacterium Streptococcus, “necrotizing fasciitis,” caused panic headlines in Britain about “flesh-eating germs” and “killer bugs.” Of the fifteen reported victims so far, thirteen have died.
A great deal has changed since the 1940s and 1950s. Strains of bacteria can cross the planet with the speed of jet travel, and populations of humans — each with their hundred trillion bacterial passengers — mingle as never before. Old-fashioned public-health surveillance programs, which used to closely study any outbreak of bacterial disease, have been dismantled, or put in abeyance, or are underfunded. The seeming triumph of antibiotics has made us careless about the restive conquered population of bacteria.
Drug companies treat the standard antibiotics as cash cows, while their best-funded research efforts currently go into antiviral and antifungal compounds. Drug companies follow the logic of the market; with hundreds of antibiotics already cheaply available, it makes little commercial sense to spend millions developing yet another one. And the market is not yet demanding entirely new antibiotics, because the resistance has not quite broken out into full-scale biological warfare. And drug research is expensive and risky. A hundred million dollars of investment in antibiotics can be wiped out by a single point-mutation in a resistant bacterium.
We did manage to kill off the smallpox virus, but none of humanity’s ancient bacterial enemies are extinct. They are all still out there, and they all still kill people. Drug companies mind their cash flow, health agencies become complaisant, people mind what they think is their own business, but bacteria never give up. Bacteria have learned to chew up, spit out, or shield themselves from any and every drug we can throw at them. They can now defeat every technique we have. The only reason true disaster hasn’t broken out is because all bacteria can’t all defeat all the techniques all at once. Yet.
There have been no major conceptual breakthroughs lately in the antibiotic field. There has been some encouraging technical news, with new techniques such as rational drug design and computer-assisted combinatorial chemistry. There may be entirely new miracle drugs just over the horizon that will fling the enemy back once again, with enormous losses. But on the other hand, there may well not be. We may already have discovered all the best antibiotic tricks available, and squandered them in a mere fifty years.
Anyway, now that the nature of their resistance is better understood, no bacteriologist is betting that any new drug can foil our ancient enemies for very long. Bacteria are better chemists than we are and they don’t get distracted.
If the resistance triumphs, it does not mean the outbreak of universally lethal plagues or the end of the human race. It is not an apocalyptic problem. What it would really mean — probably — is a slow return, over decades, to the pre-antibiotic bacterial status-quo. A return to the bacterial status-quo of the nineteenth century.
For us, the children of the miracle, this would mean a truly shocking decline in life expectancy. Infant mortality would become very high; it would once again be common for parents to have five children and lose three. It would mean a return to epidemic flags, quarantine camps, tubercular sanatariums, and leprosariums.
Cities without good sanitation — mostly Third World cities — would suffer from water-borne plagues such as cholera and dysentery. Tuberculosis would lay waste the underclass around the world. If you cut yourself at all badly, or ate spoiled food, there would be quite a good chance that you would die. Childbirth would be a grave septic risk for the mother.
The practice of medicine would be profoundly altered. Elaborate, high-tech surgical procedures, such as transplants and prosthetic implants, would become extremely risky. The expense of any kind of surgery would soar, since preventing infection would be utterly necessary but very tedious and difficult. A bad heart would be a bad heart for life, and a shattered hip would be permanently disabling. Health-care budgets would be consumed by antiseptic and hygienic programs.
Life without contagion and infection would seem as quaintly exotic as free love in the age of AIDS. The decline in life expectancy would become just another aspect of broadly diminishing cultural expectations in society, economics, and the environment. Life in the developed world would become rather pinched, wary, and nasty, while life in the overcrowded human warrens of the megalopolitan Third World would become an abattoir.
If this all seems gruesomely plausible, it’s because that’s the way our ancestors used to live all the time. It’s not a dystopian fantasy; it was the miracle of antibiotics that was truly fantastic. It that miracle died away, it would merely mean an entirely natural return to the normal balance of power between humanity and our invisible predators.
At the close of this century, antibiotic resistance is one of the gravest threats that confronts the human race. It ranks in scope with overpopulation, nuclear disaster, destruction of the ozone, global warming, species extinction and massive habitat destruction. Although it gains very little attention in comparison to those other horrors, there is nothing theoretical or speculative about antibiotic resistance. The mere fact that we can’t see it happening doesn’t mean that it’s not taking place. It is occurring, stealthily and steadily, in a world which we polluted drastically before we ever took the trouble to understand it.
We have spent billions to kill bacteria but mere millions to truly comprehend them. In our arrogance, we have gravely underestimated our enemy’s power and resourcefulness. Antibiotic resistance is a very real threat which is well documented and increasing at considerable speed. In its scope and its depth and the potential pain and horror of its implications, it may the greatest single menace that we human beings confront — besides, of course, the steady increase in our own numbers. And if we don’t somehow resolve our grave problems with bacteria, then bacteria may well resolve that population problem for us.
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Essays. FSF Columns Page 18
