At the turn of the 21st century, microbial resistance to antibiotics has become a cause célèbre, with public health experts contending that the overuse of these drugs has put us all at risk for a rising tide of super-bugs, infections so inured to treatment that they simply cannot be cured. Already, the experts point out, we have bred antibiotic-resistant strains of Staphylococcus aureus, a potentially deadly bacterium most often found in hospitals. Three other bacteria - Enterococcus faecalis, Mycobacterium tuberculosis, and Pseudomonas aeruginosa - can evade almost every one of the hundred or so antibiotics we rely on. This issue takes on new relevance in the face of anthrax scares and the overall specter of bioterrorism: as a nation of antibiotic junkies, say the powers that be, we may find these medications ineffective when we need them most.

But just when it seems we may be running out of steam with long-used antibiotics, SIGA Technologies, a New York- and Oregon-based company, has deployed a new set of strategies to stop the same old bugs. Currently, says Dennis E. Hruby, SIGA's chief scientific officer, "virtually all the antibiotics currently in use hit the same targets, attacking either bacterial cell wall or protein synthesis or membrane integrity. Because of this, when bacteria evolve resistance to one antibiotic, they often evolve resistance to entire classes of antibiotics."

The way to stay one step ahead, of course, is to introduce new medications when the old ones no longer work. In the past, researchers looked for antibiotics by screening for compounds that kill bacteria. But that method has limited utility, Hruby notes, since "almost any kind of compound that can be discovered in that manner has been discovered already, by one of our large pharmaceutical firms."

Given the lay of the land, SIGA has taken a different approach. Instead of looking at "bacteriocidal factors" that either kill bacteria or halt their reproduction, the company is targeting "virulence factors," including the toxins or properties that make people ill. "The rationale," says Hruby, "is that if you can target these pathways, you will disarm disease-causing bacteria so that they are unable to cause disease."

One SIGA strategy is to target the bacterial adhesion factors that enable microbes to latch on to human tissue, the first step in initiating disease. "When bacteria arrive in a person's body, they must interact with a mucosal surface in order to stick there," Hruby explains. "Only in that way can they colonize sufficiently to generate toxins or interfere with the function of the human host." To interfere with adhesion, SIGA has identified enzymes involved in synthesizing, extruding, and anchoring adhesive structures to bacterial cell walls. "Our strategy is production of small molecules to inhibit the enzymes involved," Hruby explains. "Denuded of their adhesive proteins, the bacteria will be unable to stick or to cause disease, and they will be cleared by the innate immune system."

The concept is especially powerful because it models the immune system itself. "Our drugs prevent bacteria from binding to tissue, and in many instances antibodies do the same. If you generate an immune response against a bacterium, those antibodies bind to the outside of the bacterium, neutralize its adhesive structures, and either clear it or allow it to be cleared by macrophages," Hruby explains. "The difference is that the antibody response takes time to develop, so you must be immunized prior to infection. But our anti-infectives will work after exposure."

One line of SIGA products, currently under development with Wyeth-Ayerst, focuses only on gram-positive bacteria, including such increasingly resistant organisms as S. aureus, E. faecalis, and Streptococcus pneumoniae, all of which are rapidly developing antibiotic resistance. Here, SIGA is going after single proteins that resemble fuzz or hair on the bacterial wall.

A second product line targets adhesion proteins on gram-negative bacteria, including such resistant bugs as Escherichia coli, Salmonella, Shigella species, and Neisseria gonorrhoeae. Here the company has set its sights on disrupting the assembly of large, complex structures known as pili, made of hundreds of different proteins put together "like a miniature Eiffel Tower with the adhesive at the top."

SIGA is also developing a broad-spectrum antibiotic that may be useful against organisms that don't fit any of these categories, such as rickettsiae and spirochetes.

Will microorganisms ultimately become resistant to SIGA's adhesion-based antibiotics, just as they have to the drugs of the past? "That is almost a given," says Hruby. "Any time you put negative selection on bacteria, they will tend to get around it through spontaneous mutation. We would like to think that our antibiotics will be less prone to resistance, however, because the enzymes we are targeting are especially essential to their structure, making them somewhat constrained in their ability to mutate." Hruby also theorizes that SIGA anti-infectives may exert a weaker negative selection pressure on bacteria than do conventional antibiotics because they are not killing the organisms, but merely disarming them. But these theories will not be tested, he admits, until the medications are widely used.

In the end, Hruby notes, resistance to anti-microbial agents will best be evaded by using medications that are carefully targeted and precise. "The broader the antibiotic used, the more likely it is that resistant microbes will emerge," he says. "We are seeing that right now with the people potentially exposed to anthrax. They are taking ciprofloxacin, one of our most powerful, broad-spectrum antibiotics; but when they do that, they are exposing every bacterium in their body to that medication, and are at risk for resistance." But, he adds, "If you have anthrax, of course you won't worry about causing resistance problems, you'll just get rid of the disease."

With more targeted medications, however, only the bacterial species being targeted would be at risk for developing any resistance at all. "When a sick individual comes in, you could use state-of-the-art diagnostics to understand what they are suffering from and deliver an antibiotic for that particular kind of bacteria," Hruby says, noting that SIGA's anti-virulence approach may be particularly conducive to specificity because each bacterial species has its own unique set of adhesive structures targeted to specific tissues and associated with different types of disease.

SIGA is considering not only anti-infectives specific to bacterial species, but also drugs that target a single organ at a time. These new therapeutics, created from benign bacterial organisms found in yogurt and cheese, are engineered to live in just a single type of tissue, Hruby explains. The microbes also function as protein factories, pumping out enzymes, antigens, or other types of anti-infective agents. "If you want to protect against sexually transmitted disease," says Hruby, "you can deploy a bacterium that lives in the vaginal tract and is engineered to elaborate a drug against, say, gonorrhea." Delivered just once, perhaps orally, this living antibiotic would travel to its target, and, working 24/7, cure or prevent disease.

For those who require longer-term antibiotic treatment, this one-dose system would be elegant indeed. The system has even been designed with an "off switch" in the form of genetically engineered markers so that physicians can bring the treatment to an end once it is no longer needed. To halt therapy, Hruby explains, SIGA scientists will deploy what they call an "inducer" microbe, one programmed to find and destroy the medication-dispensing bugs.