In May, runaway groom Andrew Speaker gave the public a crash course in drug-resistant tuberculosis. It turned out that Speaker wasn't infected with the worst form of TB after all. But he's done us a favor by making us think about antibiotic resistance to infection. This is one of those problems, like global warming, that is creepily creeping up on us. Around the world, drug-resistant strains of tuberculosis are proliferating. The superbug MRSA (or methicillin-resistant Staphylococcus aureus) is now found in 34 of every 1,000 hospital patients. And vancomycin-resistant enterococci—also bad bacteria—is responsible for roughly a third of infections in hospital intensive-care units.
These warning signs, highlighted by a recent spate of editorials (subscription required), articles, and blogs, may make us wish for a gorillacillin—a superdrug—that could destroy any bug under the sun. But as the National Academy of Sciences pointed out last year, such a remedy is unlikely to emerge. And if one did, it would probably be used so widely that resistant strains would quickly evolve. Instead, the future seems to lie with treatments that target specific bacteria by taking cues from how they behave in nature, modulating the human immune system, or intervening boldly in bacterial genetics. Some of these approaches may substitute for antibiotics; others could extend the usefulness of the drugs we have. Here are some of the best big ideas ranked on a scale of 1 to 10, based on their potential promise and sheer intellectual chutzpah.
1. Mimicking Nature
In nature, bacteria often use highly targeted proteins called bacteriocins to kill their close relatives (typically when times are tough and resources scarce). Bacteriocins are widespread, so it's relatively easy and cheap to find the one that could kill, say, the causative agent of anthrax or plague, says Peg Riley of the University of Massachusetts, Amherst.
Riley's group is running animal trials on bacteriocins to fight urinary tract infections, and in vitro trials to treat ear infections and conjunctivitis. In the future, she envisions a pharma shelf that contains "narrow spectrum bacteriocins for every major human infectious disease." Because bacteriocins target specific bacteria, resistant strains would take longer to evolve and spread, Riley argues. On the other hand, more targeted therapies mean that doctors would need to know exactly what they're shooting at. So this strategy may be widely practical only if and when faster diagnostic tools—like chip-based technologies—come on line.
2. Eating Bugs
Bacteriophages are viruses that can infect and kill specific types of bacteria (the word phage is derived from the Greek "to eat"). Like bacteriocins, phages are widespread in nature, meaning that drug candidates would probably be relatively easy to find. Phages are already used in the food industry: The Canadian company Biophage Pharma Inc. sells a product called Listex, which can be added to cold cuts and cheeses to kill listeria. The company is also working on a product that hospitals could spray on surfaces to kill MRSA—or perhaps spray into the nasal passages of people who carry this superbug. Phage treatment for infection is currently available in Soviet Georgia. But many Western experts worry about the quality and safety of the viruses used there. Experts also view phages as something of a wild card, since they can promote the reshuffling of DNA. Phages won't gain ground in Western hospitals and clinics until their effect on specific bacteria is studied a lot more thoroughly.
3. Controlling Crowds
Bacteria compete with one another—and sometimes we can reap the benefits. Under normal circumstances, good bacteria on our skin and in our mouths and guts help to keep out pathogenic invaders. The Wisconsin-based company ConjuGon is working on a treatment for chronic urinary tract infections that harnesses a similar principle. Its method builds on research that suggests introducing benign bacteria into the bladder—which is normally bacteria-free—may help to crowd out bad bugs and prevent urinary tract infections. Such a treatment would be especially good for patients with permanent catheters, who often get several UTIs a year, the company says. Swedish researchers have also explored whether bacterial crowding might be used to prevent ear infections. In general, toying with bacterial populations can be tricky business, just as messing with ecosystems is. And companies will need to worry about preventing unintended side effects like inflammation.
4. Blaming the Victim
Our immune systems overreact to many bacterial invaders, and in the process cause as much or more harm than the bugs themselves. Such is the case with tuberculosis, meningitis, rheumatic fever, pneumonia, and septicemic plague, say Elisa Margolis and Bruce Levin of Emory University. They argue for manipulating the body's immune response. In 2001, Eli Lilly received FDA approval for a drug called Xigris, which is designed to counter the body's over-response to sepsis (or systemic inflammation due to infection). But Xigris has remained controversial. And so far, other attempts to develop immune-modulating drugs for bacterial infections seem to have come up short. Partly, this is because the immune system is so complex—it is hard to know precisely which cells and molecules it's mobilizing at any given time. Real-time, computer-assisted monitoring of a patient's immune system may be required for this approach to gain traction, Margolis and Levin recognize. At least at first, their strategy thus would probably be relevant to only the sickest patients.
5. Stopping Evolution:
What if we could intervene genetically and stop bacteria from becoming antibiotic-resistant? The traditional view is that drug-resistant bacteria are created by random mutation. Recently, however, Floyd Romesberg of the Scripps Research Institute has found that antibiotics can cause new mutations in some bacteria by sending them into SOS orbit, in which they turn on a mutation-inducing gene. By inhibiting this gene in vitro, Romesberg has managed to prevent bacteria from becoming resistant to the antibiotics ciprofloxacin and rifampicin. If an inhibitor drug for humans could be developed, he says, it could be given in conjunction with antibiotics and might help to extend their usefulness.
Romesberg's strategy is tantamount to sticking a finger in the eye of evolution—and in theory it holds great appeal. In practice, however, a drug that inhibits a mutation-causing mechanism would probably be hard to develop. Such a drug would also help only people who started out with nonresistant bugs—like those for whom antibiotics initially worked and then stopped—rather than those initially infected with a resistant strain.
Meanwhile, meddling with evolution is also a low-tech game. The rest of us can do our part by avoiding broad-spectrum antibiotics and antibacterial soaps and wipes (unless we happen to work in an operating room) and by buying antibiotic-free meat. While we're waiting on the big ideas, the small measures are all we've got.