rom the air we breathe to the food we eat to the ground and floors we walk on, bacteria are everywhere. They are the true masters of the Earth, among whom we survive, perhaps, more precariously than we care to admit. This point was forcibly hammered home in the 1330s, when the bacteria Pasteurella pestis, a.k.a. the bubonic plague or Black Death, wiped out a third of the population of Europe. Today, the Plague is common in rodents throughout the world, but human cases are rare (only 10-15 cases per year in the United States, and 1,000-3,000 per year worldwide), and with a mortality rate of only 14% given prompt antibiotic treatment, human plague deaths are rarer still.

Much of the credit for this goes to Scottish microbiologist Alexander Fleming, who in 1928, through a combination of blind luck and poor experimental hygiene, discovered a mold--Penicillium notatum--which was capable of killing off bacteria. This was actually not the world's first antibiotic; since ancient times, physicians have helped the healing of wounds with honey and spiderwebs and various herbal pastes and poultices, including molds. But penicillin was the first such drug to be studied closely, industrially refined, concentrated and pressed into edible tablets for the bodywide treatment of infection.

This idea was not widely implemented until World War II.  Allied doctors with thousands upon thousands of wounded men saw the survival benefits of oral antibiotic treatment.  Penicillin-filled soldiers were able to avoid infection, healing more quickly and more completely than even the doctors themselves could believe. Penicillin was hailed as a wonder drug, and the age of antibiotics was born.

War breeds medicine's new weapon

Soon, researchers were isolating, synthesizing and mass-producing the bacteria-killing substances from all the age-old remedies and more, adding new antibiotics like erythromycin and tetracycline (1952) to the armories of 20th-century medicine. Which was a good thing, because penicillin turned out to be poisonous only to Gram-positive bacteria--those with a thick layer of the substance peptidoglycan in their outer wall.

 Infectious agents such as Mycobacterium tuberculosis--the cause of the progressive lung disease tuberculosis--were not affected by it at any dose. But as the latter half of the 20th Century unfolded, antibiotics specific to every major bacterial pathogen were found, and dread diseases such as tuberculosis, cholera and bubonic plague all but vanished from the developed world. Bacterial infection, a source of mortal terror since before the dawn of civilization, was suddenly demoted to the level of mere inconvenience. Moreover, many of the antibiotics discovered were "broad-spectrum" treatments, capable of killing off virtually any bacterium at all, often with few if any side effects in human beings.

That turned out to be a good thing, too, because bacteria, the most metabolically inventive organisms on the planet, have had nearly four billion years' experience in adapting to chemically unfriendly environments. Since it takes an average bacterium only about 20 minutes to reproduce itself, as opposed to years or decades for higher animals, bacteria are capable of evolving hundreds of thousands of times faster.  The presence of poisons in the environment turns out to be an ideal driver of natural selection, because the weak die off quickly, while the strong--the resistant--may hang on long enough to reproduce, passing their slightly better genes along to an exponentially growing family of descendants. Then the weaker descendants die off, while their superior siblings survive. .. Whatever doesn't kill you makes you stronger, yeah. Rapidly.

Bacteria have another trick, too: unlike higher animals, they're able to share and trade ring-shaped DNA segments called plasmids--the genetic equivalent of software plug-ins or card game booster packs, which contain important new talents, such as the ability to metabolize a dangerous substance. And with surprising altruism, even bacteria of different species can and do help each other out this way, so doctors began to find that if some hapless patient quit taking his medicine before an infection was 100% cured, he not only incubated a strain of resistant microbes inside his own body, but sometimes wound up educating the unrelated strains inhabiting his home, office, car and family.

By the 1960s, we began to hear rumors of penicillin-resistant strains of syphilis and gonorrhea--diseases often acquired and treated in secret, away from medical scrutiny. Soon, though, other illnesses were showing similar signs of trouble. Of course, any genetic trait requires time and energy to support, so these resistances often vanished when a new class of drugs were brought to bear. Bugs which had learned to live with penicillin would generally succumb to something stronger like tetracycline, which also gave the penicillin a chance to "rest" while its enemies forgot about it. For a while, it seemed this drug rotation strategy might keep the world healthy forever.

Alas, evolution is smarter than that. In order to survive and reproduce, bacteria rely on a series of metabolic tools and processes--their internal life-support systems, their metabolism. Antibiotics operate by disrupting these. Any break in the metabolic chain will suffice to kill off an infection, and every family of antibiotics targets a different life support process, so it seems reasonable to suppose that no single bacterium could be immune to everything. But at heart these processes are all molecular: an enzyme breaks down sugar molecules for energy, another brings together amino acids to form a protein, and so on. All of this is made possible by tiny molecular motors called efflux pumps, which dot the surface of a bacterium's outer membrane, and which carefully and constantly control the critter's internal chemistry. Food, water and electrolytes are passed inside for the grand construction project that will let the cell reproduce and divide, while toxins and waste products are pumped out.

The supergerms deliver a stalemate

By the early 1990s, the phenomenon of multiple drug resistance was well documented; some bacteria were immune not only to antibiotics from wildly different families, but to new drug families they had never been exposed to in the first place! The bacteria had done an end-run around our defenses; they had simply increased the number of efflux pumps in their membranes, and were getting rid of everything they didn't immediately need or want inside them. By 1997, doctors were seeing their final defensive lines crumble, as enemy staph and strep bacteria--ubiquitous sources of human infection--began to overcome vancomycin. That's the broadest and most powerful antibiotic known, and is toxic enough to humans that it had long been reserved as a drug of last resort. For the first time in nearly half a century, the developed world faced bacterial infections that were literally incurable. And that was three and four years ago.

Not to be alarmist, but this is no longer a science fictional scenario. This is no longer an issue we can push off into some indefinite future. In the past few years, our farms and hospitals--ostensibly civilization's life support centers--have become the spawning grounds of supergerms, which are immune to every treatment we can throw at them. Our prisons and homeless shelters are even worse, and countries like Russia, which have fallen on hard times, can now boast tuberculosis and other deadly-again diseases as their largest export commodity. According to the Centers for Disease Control, almost 70,000 Americans died of bacterial infection in 1998, and last year's age-adjusted rates were up 4.8% for septicemia, and roughly 2.3% for pneumonia. If you haven't known or heard of someone who's died this way, chances are you soon will.

That's the bad news. The good news is that there are simple things you can do to protect yourself. Staying out of the hospital is a good first step; outpatient care is usually a fine alternative. Also, use antibiotics only and exactly as prescribed by your doctor, and throw away those silly antibacterial hand soaps; unless you're scrubbing in for surgery, their health benefits are entirely negative. On a more subtle note, U.S. factory-farming practices are increasingly churning out meat products contaminated with resistant bacteria. When was the last time you felt safe eating raw eggs or undercooked meat? Organic produce isn't really that much more expensive, and may prove substantially safer in the long run. Ask a victim of Mad Cow Disease! Also, support for strong public health programs should be seen as a medical issue, rather than a political one on the illusory liberal-conservative scale.

The other good news is that antibiotic research, after years of slumber, has reawakened with several promising lines of attack, including new drugs which target and shut down the efflux pumps themselves. And as 20th-century style drug research (a.k.a. "the bug juice lottery") gives way to medicines designed from the molecular level up, we'll almost certainly discover new Achilles heels in the machineries of bacterial life, and also new ways to immunize our own bodies. The golden age may yet be restored.

For a while, anyway; given the speed of evolution and the ubiquity of bacteria in our environment, this is a war we can stalemate, but never win.

---

Wil McCarthy is a rocket guidance engineer, robot designer, science fiction author and occasional aquanaut. He has contributed to three interplanetary spacecraft, five communication and weather satellites, a line of landmine-clearing robots, and some other "really cool stuff" he can't tell us about. His short fiction has graced the pages of Analog, Asimov's, Science Fiction Age and other major publications, and his novel-length works include Aggressor Six, the New York Times Notable Bloom, and The Collapsium.

Questions

1. Explain why  antibiotics are effective against bacteria?
2. Which bacteria are affected by penicillin?
3. How does antibiotic resistance develop?
4. What can you do to aviod "super bugs"?