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F&SF Science Column #15: "Bitter Resistance"

Two hundred thousand bacteria could easily lurk under the top half of this semicolon; but for the sake of focussing on a subject that's too often out of sight and out of mind, let's pretend otherwise. Let's pretend that a bacterium is about the size of a railway tank car.

Now that our fellow creature the bacterium is no longer three microns long, but big enough to crush us, we can get a firmer mental grip on the problem at hand. The first thing we notice is that the bacterium is wielding long, powerful whips that are corkscrewing at a blistering 12,000 RPM. When it's got room and a reason to move, the bacterium can swim ten body-lengths every second. The human equivalent would be sprinting at forty miles an hour.

The butt-ends of these spinning whips are firmly socketed inside rotating, proton-powered, motor-hubs. It seems very unnatural for a living creature to use rotating wheels as organs, but bacteria are serenely untroubled by our parochial ideas of what is natural.

The bacterium, constantly chugging away with powerful interior metabolic factories, is surrounded by a cloud of its own greasy spew. The rotating spines, known as flagella, are firmly embedded in the bacterium's outer hide, a slimy, lumpy, armored bark. Studying it closely (we evade the whips and the cloud of mucus), we find the outer cell wall to be a double-sided network of interlocking polymers, two regular, almost crystalline layers of macromolecular chainmail, something like a tough plastic wiffleball.

The netted armor, wrinkled into warps and bumps, is studded with hundreds of busily sucking and spewing orifices. These are the bacterium's "porins," pores made from wrapped-up protein membrane, something like damp rolled-up newspapers that protrude through the armor into the world outside.

On our scale of existence, it would be very hard to drink through a waterlogged rolled-up newspaper, but in the tiny world of a bacterium, osmosis is a powerful force. The osmotic pressure inside our bacterium can reach 70 pounds per square inch, five times atmospheric pressure. Under those circumstances, it makes a lot of sense to be shaped like a tank car.

Our bacterium boasts strong, highly sophisticated electrochemical pumps working through specialized fauceted porins that can slurp up and spew out just the proper mix of materials. When it's running its osmotic pumps in some nutritious broth of tasty filth, our tank car can pump enough juice to double in size in a mere twenty minutes. And there's more: because in that same twenty minutes, our bacterial tank car can build in entire duplicate tank car from scratch.

Inside the outer wall of protective bark is a greasy space full of chemically reactive goo. It's the periplasm. Periplasm is a treacherous mess of bonding proteins and digestive enzymes, which can yank tasty fragments of gunk right through the exterior hide, and break them up for further assimilation, rather like chemical teeth. The periplasm also features chemoreceptors, the bacterial equivalent of nostrils or taste- buds.

Beneath the periplasmic goo is the interior cell membrane, a tender and very lively place full of elaborate chemical scaffolding, where pump and assembly-work goes on.

Inside the interior membrane is the cytoplasm, a rich ointment of salts, sugars, vitamins, proteins, and fats, the tank car's refinery treasure-house.

If our bacterium is lucky, it has some handy plasmids in its custody. A plasmid is an alien DNA ring, a kind of fly-by-night genetic franchise which sets up work in the midst of somebody else's sheltering cytoplasm. If the bacterium is unlucky, it's afflicted with a bacteriophage, a virus with the modus operandi of a plasmid but its own predatory agenda.

And the bacterium has its own native genetic material. Eukaryotic cells -- we humans are made from eukaryotic cells -- possess a neatly defined nucleus of DNA, firmly coated in a membrane shell. But bacteria are prokaryotic cells, the oldest known form of life, and they have an attitude toward their DNA that is, by our standards, shockingly promiscuous. Bacterial DNA simply sprawls out amid the cytoplasmic goo like a circular double-helix of snarled and knotted Slinkies.

Any plasmid or transposon wandering by with a pair of genetic shears and a zipper is welcome to snip some data off or zip some data in, and if the mutation doesn't work, well, that's just life. A bacterium usually has 200,000 or so clone bacterial sisters around within the space of a pencil dot, who are more than willing to take up the slack from any failed experiment in genetic recombination. When you can clone yourself every twenty minutes, shattering the expected laws of Darwinian heredity merely adds spice to life.

Bacteria live anywhere damp. In water. In mud. In the air, as spores and on dust specks. In melting snow, in boiling volcanic springs. In the soil, in fantastic numbers. All over this planet's ecosystem, any liquid with organic matter, or any solid foodstuff with a trace of damp in it, anything not salted, mummified, pickled, poisoned, scorching hot or frozen solid, will swarm with bacteria if exposed to air. Unprotected food always spoils if it's left in the open. That's such a truism of our lives that it may seem like a law of physics, something like gravity or entropy; but it's no such thing, it's the relentless entrepreneurism of invisible organisms, who don't have our best interests at heart.

Bacteria live on and inside human beings. They always have; bacteria were already living on us long, long before our species became human. They creep onto us in the first instants in which we are held to our mother's breast. They live on us, and especially inside us, for as long as we live. And when we die, then other bacteria do their living best to recycle us.

An adult human being carries about a solid pound of commensal bacteria in his or her body; about a hundred trillion of them. Humans have a whole garden of specialized human-dwelling bacteria -- tank-car E. coli, balloon-shaped staphylococcus, streptococcus, corynebacteria, micrococcus, and so on. Normally, these lurkers do us little harm. On the contrary, our normal human-dwelling bacteria run a kind of protection racket, monopolizing the available nutrients and muscling out other rival bacteria that might want to flourish at our expense in a ruder way.

But bacteria, even the bacteria that flourish inside us all our lives, are not our friends. Bacteria are creatures of an order vastly different from our own, a world far, far older than the world of multicellular mammals. Bacteria are vast in numbers, and small, and fetid, and profoundly unsympathetic.

So our tank car is whipping through its native ooze, shuddering from the jerky molecular impacts of Brownian motion, hunting for a chemotactic trail to some richer and filthier hunting ground, and periodically peeling off copies of itself. It's an enormously fast-paced and frenetic existence. Bacteria spend most of their time starving, because if they are well fed, then they double in number every twenty minutes, and this practice usually ensures a return to starvation in pretty short order. There are not a lot of frills in the existence of bacteria. Bacteria are extremely focussed on the job at hand. Bacteria make ants look like slackers.

And so it went in the peculiar world of our acquaintance the tank car, a world both primitive and highly sophisticated, both frenetic and utterly primeval. Until an astonishing miracle occurred. The miracle of "miracle drugs," antibiotics.

Sir Alexander Fleming discovered penicillin in 1928, and the power of the sulfonamides was recognized by drug company researchers in 1935, but antibiotics first came into general medical use in the 1940s and 50s. The effects on the hidden world of bacteria were catastrophic. Bacteria which had spent many contented millennia decimating the human race were suddenly and swiftly decimated in return. The entire structure of human mortality shifted radically, in a terrific attack on bacteria from the world of organized intelligence.

At the beginning of this century, back in the pre-antibiotic year of 1900, four of the top ten leading causes of death in the United States were bacterial. The most prominent were tuberculosis ("the white plague," *Mycobacterium tuberculosis*) and pneumonia (*Streptococcus pneumoniae,* *Pneumococcus*). The death rate in 1900 from gastroenteritis (*Escherichia coli,* various *Campylobacter* species, etc.) was higher than that for heart disease. The nation's number ten cause of death was diphtheria (*Corynebacterium diphtheriae*). Bringing up the bacterial van were gonorrhea, meningitis, septicemia, dysentery, typhoid fever, whooping cough, and many more.

At the end of the century, all of these festering bacterial afflictions (except pneumonia) had vanished from the top ten. They'd been replaced by heart disease, cancer, stroke, and even relative luxuries of postindustrial mortality, such as accidents, homicide and suicide. All thanks to the miracle of antibiotics.

Penicillin in particular was a chemical superweapon of devastating power. In the early heyday of penicillin, the merest trace of this substance entering a cell would make the hapless bacterium literally burst. This effect is known as "lysing."

Penicillin makes bacteria lyse because of a chemical structure called "beta-lactam." Beta-lactam is a four-membered cyclic amide ring, a molecular ring which bears a fatal resemblance to the chemical mechanisms a bacterium uses to build its cell wall.

Bacterial cell walls are mostly made from peptidoglycan, a plastic- like molecule chained together to form a tough, resilient network. A bacterium is almost always growing, repairing damage, or reproducing, so there are almost always raw spots in its cell wall that require construction work.

It's a sophisticated process. First, fragments of not-yet-peptided glycan are assembled inside the cytoplasm. Then the glycan chunks are hauled out to the cell wall by a chemical scaffolding of lipid carrier molecules, and they are fitted in place. Lastly, the peptidoglycan is busily knitted together by catalyzing enzymes and set to cure.

But beta-lactam is a spanner in the knitting-works, which attacks the enzyme which links chunks of peptidoglycan together. The result is like building a wall of bricks without mortar; the unlinked chunks of glycan break open under osmotic pressure, and the cell spews out its innards catastrophically, and dies.

Gram-negative bacteria, of the tank-car sort we have been describing, have a double cell wall, with an outer armor plus the inner cell membrane, rather like a rubber tire with an inner tube. They can sometimes survive a beta-lactam attack, if they don't leak to death. But gram-positive bacteria are more lightly built and rely on a single wall only, and for them a beta-lactam puncture is a swift kiss of death.

Beta-lactam can not only mimic, subvert and destroy the assembly enzymes, but it can even eat away peptide-chain mortar already in place. And since mammalian cells never use any peptidoglycans, they are never ruptured by penicillin (although penicillin does sometimes provoke serious allergic reactions in certain susceptible patients).

Pharmaceutical chemists rejoiced at this world-transforming discovery, and they began busily tinkering with beta-lactam products, discovering or producing all kinds of patentable, marketable, beta-lactam variants. Today there are more than fifty different penicillins and seventy-five cephalosporins, all of which use beta-lactam rings in one form or another.

The enthusiastic search for new medical miracles turned up substances that attack bacteria through even more clever methods. Antibiotics were discovered that could break-up or jam-up a cell's protein synthesis; drugs such as tetracycline, streptomycin, gentamicin, and chloramphenicol. These drugs creep through the porins deep inside the cytoplasm and lock onto the various vulnerable sites in the RNA protein factories. This RNA sabotage brings the cell's basic metabolism to a seething halt, and the bacterium chokes and dies.

The final major method of antibiotic attack was an assault on bacterial DNA. These compounds, such as the sulphonamides, the quinolones, and the diaminopyrimidines, would gum up bacterial DNA itself, or break its strands, or destroy the template mechanism that reads from the DNA and helps to replicate it. Or, they could ruin the DNA's nucleotide raw materials before those nucleotides could be plugged into the genetic code. Attacking bacterial DNA itself was the most sophisticated attack yet on bacteria, but unfortunately these DNA attackers often tended to be toxic to mammalian cells as well. So they saw less use. Besides, they were expensive.

In the war between species, humanity had found a full and varied arsenal. Antibiotics could break open cell walls, choke off the life-giving flow of proteins, and even smash or poison bacterial DNA, the central command and control center. Victory was swift, its permanence seemed assured, and the command of human intellect over the realm of brainless germs was taken for granted. The world of bacteria had become a commercial empire for exploitation by the clever mammals.

Antibiotic production, marketing and consumption soared steadily. Nowadays, about a hundred thousand tons of antibiotics are manufactured globally every year. It's a five billion dollar market. Antibiotics are cheap, far cheaper than time-consuming, labor-intensive hygienic cleanliness. In many countries, these miracle drugs are routinely retailed in job-lots as over-the-counter megadosage nostrums.

Nor have humans been the only mammals to benefit. For decades, antibiotics have been routinely fed to American livestock. Antibiotics are routinely added to the chow in vast cattle feedlots, and antibiotics are fed to pigs, even chickens. This practice goes on because a meat animal on antibiotics will put on poundage faster, and stay healthier, and supply the market with cheaper meat. Repeated protests at this practice by American health authorities have been successfully evaded in courts and in Congress by drug manufacturers and agro-business interests.

The runoff of tainted feedlot manure, containing millions of pounds of diluted antibiotics, enters rivers and watersheds where the world's free bacteria dwell.

In cities, municipal sewage systems are giant petri-dishes of diluted antibiotics and human-dwelling bacteria.

Bacteria are restless. They will try again, every twenty minutes. And they never sleep.

Experts were aware in the 1940s and 1950s that bacteria could, and would, mutate in response to selection pressure, just like other organisms. And they knew that bacteria went through many generations very rapidly, and that bacteria were very fecund. But it seemed that any bacteria would be very lucky to mutate to successfully resist even one antibiotic. Compounding that luck by evolving to resist two antibiotics at once seemed well-nigh impossible. Bacteria were at our mercy. They didn't seem any more likely to resist penicillin and tetracycline than a rainforest can resist bulldozers and chainsaws.

However, thanks to convenience and the profit motive, once- miraculous antibiotics had become a daily commonplace. A general chemical haze of antibiotic pollution spread across the planet. Titanic numbers of bacteria, in all niches of bacterial life, were being given an enormous number of chances to survive antibiotics.

Worse yet, bacteriologists were simply wrong about the way that bacteria respond to a challenge.

Bacteria will try anything. Bacteria don't draw hard and fast intellectual distinctions between their own DNA, a partner's DNA, DNA from another species, virus DNA, plasmid DNA, and food.

This property of bacteria is very alien to the human experience. If your lungs were damaged from smoking, and you asked your dog for a spare lung, and your dog, in friendly fashion, coughed up a lung and gave it to you, that would be quite an unlikely event. It would be even more miraculous if you could swallow a dog's lung and then breathe with it just fine, while your dog calmly grew himself a new one. But in the world of bacteria this kind of miracle is a commonplace.

Bacteria share enormous amounts of DNA. They not only share DNA among members of their own species, through conjugation and transduction, but they will encode DNA in plasmids and transposons and packet-mail it to other species. They can even find loose DNA lying around from the burst bodies of other bacteria, and they can eat that DNA like food and then make it work like information. Pieces of stray DNA can be swept all willy-nilly into the molecular syringes of viruses, and injected randomly into other bacteria. This fetid orgy isn't what Gregor Mendel had in mind when he was discovering the roots of classical genetic inheritance in peas, but bacteria aren't peas, and don't work like peas, and never have. Bacteria do extremely strange and highly inventive things with DNA, and if we don't understand or sympathize, that's not their problem, it's ours.

Some of the best and cleverest information-traders are some of the worst and most noxious bacteria. Such as *Staphylococcus *(boils). *Haemophilus* (ear infections). *Neisseria *(gonorrhea). Pseudomonas (abcesses, surgical infections). Even *Escherichia,* a very common human commensal bacterium.

When it comes to resisting antibiotics, bacteria are all in the effort together. That's because antibiotics make no distinctions in the world of bacteria. They kill, or try to kill, every bacterium they touch.

If you swallow an antibiotic for an ear infection, the effects are not confined to the tiny minority of toxic bacteria that happen to be inside your ear. Every bacterium in your body is assaulted, all hundred trillion of them. The toughest will not only survive, but they will carefully store, and sometimes widely distribute, the genetic information that allowed them to live.

The resistance from bacteria, like the attack of antibiotics, is a multi-pronged and sophisticated effort. It begins outside the cell, where certain bacteria have learned to spew defensive enzymes into the cloud of slime that surrounds them -- enzymes called beta-lactamases, specifically adapted to destroy beta-lactam, and render penicillin useless. At the cell-wall itself, bacteria have evolved walls that are tougher and thicker, less likely to soak up drugs. Other bacteria have lost certain vulnerable porins, or have changed the shape of their porins so that antibiotics will be excluded instead of inhaled.

Inside the wall of the tank car, the resistance continues. Bacteria make permanent stores of beta-lactamases in the outer goo of periplasm, which will chew the drugs up and digest them before they ever reach the vulnerable core of the cell. Other enzymes have evolved that will crack or chemically smother other antibiotics.

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 lethal 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.

-- Bruce Sterling