Battle-Hardened Bacteria

When Andrew Speaker boarded an Air France flight for Paris last month carrying a form of extensively drug-resistant tuberculosis, he became a global pariah--both for the lethal bug in his system and for the folly of exposing other people to it. But while Speaker may have been reckless, the blame for the emergence of drug-resistant bugs like the one he is incubating falls partly on the rest of us. For years public-health officials have been raising the alarm about how our overreliance on antibiotics is breeding a generation of superbugs, increasingly resistant to the medicines designed to kill them. The problem has only gotten worse as antibiotic use has expanded to agriculture, where cattle, chicken and fish are routinely treated with the drugs to keep infectious diseases in check.

According to the Centers for Disease Control and Prevention, more than 70% of the bacteria that cause infections in hospitals are resistant to at least one antibiotic. Methicillin-resistant Staphylococcus aureus (MRSA), which causes boils or pimples on the skin, is only the latest superbug to make the rounds and has appeared in dozens of high school and college athletic locker rooms, as well as in three NFL locker rooms. Drug-resistant tuberculosis cases, including those of the variety affecting Speaker, have risen along with peaks in AIDS cases, as people with weakened immune systems are especially vulnerable to infection with multiple bugs.

The only way to thwart the bacteria, say public-health officials, is to curb the use of antibiotics. That's not likely to happen, with antibacterial hand sanitizers now in handy pocket packs and few folks willing to tough out a throat or ear infection without pharmaceutical help. The more the bugs come into contact with such agents, the faster bacteria find ways to mutate around them.

And that points to a fundamental weakness of current antibiotics. All exploit the fact that the best agents to kill bacteria come from other bacteria. Each species makes toxins that can either kill other species or arrest their growth, and existing antibiotics are modified versions of these natural defenses. But that is just the kind of biological arms race that microbes and other living things excel at adapting to. So researchers working on the next generation of antibiotics are taking advantage of new knowledge about bacterial genetics and a better understanding of the resistance process to stay one step ahead of the ever changing bugs.

One way to do this is to confuse the bacteria, hitting them with not just one natural toxin but two. At Vertex Pharmaceuticals in Cambridge, Mass., scientists are developing a new class of antibiotics that targets a pair of enzymes the microbes depend on to copy their genes and reproduce. Adapting in two directions at once slows down the bacteria enough to give the drug time to work. "Mathematically, it becomes much harder for the bacteria to develop resistance to different targets at the same time," says Dr. John Alam, the company's chief medical officer.

Another strategy is to ambush the bacteria with an unlikely ally: viruses. Vincent Fischetti at Rockefeller University is enlisting the help of bacteriophages, viruses that infect only bacterial cells, leaving human ones alone. They hijack the bacterium's genetic machinery and within minutes start to pump out hundreds of copies of themselves. When enough progeny build up inside the cell, the phages produce an enzyme that chews through the cell wall, causing it to explode with the force of a popping champagne cork and spew out the viral intruders.

Treating humans with live viruses--even ones that shouldn't harm us--is always risky, so Fischetti decided to isolate just the bacteria-puncturing enzyme and use it to kill bacteria from the outside. So far, he has developed compounds against pneumococcus, streptococcus and anthrax and hopes to eventually treat infected patients by squirting the enzymes in nasal-spray form weekly.

None of these agents are quite ready for the pharmacy yet, and until they are, researchers are focusing on new ways to maximize the power of drugs we do have. By studying bacterial DNA, scientists at the Naval Research Laboratory are decoding the genetic battle plans that the bugs use to develop resistance. These secrets can help doctors prescribe antibiotics more effectively by knowing which strains are most susceptible to which drugs.

As the TB scare reminded us, that's important in a world in which superbugs can quickly go global. Bacteria may be resourceful things, but science, while slower, can be smarter. It's just a matter of knowing your enemy--and packing the right weapons. [This article contains a complex diagram. Please see hardcopy or pdf.] USING A VIRUS TO ATTACK BACTERIA 1 A bacteriophage is a virus that infects bacteria but not human cells

Bacteriophage

Genes

2 It inserts its genetic material into a bacterial cell

Bacterium

Viral genes

3 The bacterium is hijacked into producing new viruses

4 After about 45 minutes, the viruses produce a lytic enzyme, which causes the bacterial cell wall to burst

5 The enzyme can be purified from these viruses or manufactured to be used as an antibiotic-like agent to kill bacteria

Lytic enzyme

Ruptured bacterial cell wall

Source: Vincent Fischetti, Ph.D., Rockefeller University

TIME Diagram by Joe Lertola