Illustration by Eric PiatkowskiImagine that 23,000 Americans have been wiped out in a terrorist act. “You can rest assured,” says David Perlin, “that we’d be aggressively addressing that threat.” The same number of Americans, and perhaps significantly more, die each year from antibiotic-resistant infections, most of which are acquired in U.S. hospitals. Yet our collective response has been anything but aggressive. As executive director of the Public Health Research Institute at Rutgers New Jersey Medical School, Perlin says that if we don’t ramp up our efforts to resolve the problem, we could find ourselves unwittingly thrust back into the pre-antibiotic era, in which half of all infectious diseases ended in death.
Because of the widespread overuse and misuse of antibiotics, disease-causing bacteria are becoming increasingly resistant, and at an accelerating rate, to the drugs designed to attack them. Meanwhile, most major pharmaceutical companies are getting out of the antibiotics business to concentrate their research and development on more profitable drugs. A week’s worth of antibiotics, for instance, might cost hundreds of dollars, but drugs for chronic conditions may cost thousands of dollars per patient. Clearly, the antibiotics crisis isn’t going to be resolved by the free market alone.
To help overcome the problem, Rutgers recently announced a $26 million, five-year research program funded by the National Institutes of Health (NIH), which is intended to help invigorate the drug pipeline by jump-starting the development of new antibiotics to replace those that have become ineffective by resistant bacteria. Led by Perlin, an infectious disease expert, the initiative is a public-private partnership that could serve as the model for antibiotic development in the 21st century. As part of the NIH Centers of Excellence for Translational Research, researchers from Rutgers and other institutions will identify targets—vulnerabilities in disease-causing bacteria—for potential antibiotics as well as pinpoint the small molecules that could be developed into antibiotics to inhibit those targets. If the new drugs, aimed specifically at multidrug-resistant bacteria (the so-called superbugs), are deemed sufficiently promising, they will be developed commercially with pharmaceutical partners.
The partnership, says Perlin, is designed to “bridge major gulfs in the drug-development process.” Although academics are quite good at finding molecules with the potential to become successful antibiotics, they often lack the resources to conduct advanced preclinical studies, he says. And drug companies are reluctant to invest in costly clinical trials when so many potential antibiotics fail at that stage. By providing first-class researchers from academia and the pharmaceutical industry with advanced resources for drug development, the partnership should get new antibiotics into the pipeline more quickly and efficiently than if either of the two groups was working alone.
The researchers will zero in on developing new classes of antibiotics—drugs that work in new ways—as opposed to creating variations on the same types of drugs in use for years. (“If you have the same drug class, often you’ll have the same effete,” Perlin says.) Richard Ebright, a principal investigator at the Waksman Institute of Microbiology and professor of chemistry and chemical biology at Rutgers and a participant in the partnership, is developing a series of drugs that inhibits the production of RNA polymerase, which he calls “a bacterial machine for making RNA” (one of two molecules found in all cells; the other is DNA). If he and his team are successful, these new drugs could sidestep the problem of resistance by making it difficult for bacteria to modify themselves without shutting down that essential RNA machine.
Ebright’s work offers a tantalizing glimpse into a possible future where superbugs’ ability to develop resistance is shut off. But until that day arrives (assuming the bugs won’t outsmart us as they always have), resistance will remain a global threat unless we make a drastic change in the way we use antibiotics.
To fully address the problem of resistance, though, Perlin and Ebright believe that we have to move away from monotherapy—the use of one antibiotic against a specific infection—to multiple dosing, a regimen already in place against HIV and tuberculosis. It’s a matter of mathematics, Ebright says: “The frequency of spontaneous random resistance to a useful antibacterial agent is in the range of 1 in 100 million to 1 in 100 billion. That doesn’t sound like a lot, but in any one person, in any given infection, there can be as many as a billion bacterial cells.” Prescribing two antibiotics, each attacking a different target, can change those odds from 1 in 100 billion to 1 in 100 billion squared, dramatically diminishing the odds of a resistance event developing.
It’s a given that the more we expose ourselves to antibiotics, the more likely that the bacteria they target will develop resistance. So it’s no wonder that Perlin cites the widespread application of antibiotics as growth-enhancers in farm animals as a potential disaster. Overuse on the human end is equally problematic. To fight it, Dorothy McCoy, a clinical assistant professor in the Department of Pharmacy Practice and Administration at the Rutgers Ernest Mario School of Pharmacy, sees a big role for pharmacists. She supports the enhancement of hospital stewardship programs in which pharmacists review physicians’ orders for antibiotics to make sure those orders are appropriate. And Perlin believes stewardship is essential. We must stratify antibiotics, carefully protecting those drugs we can’t afford to lose. For years, the antibiotic vancomycin was strictly guarded in hospitals because it remains one of the few drugs still effective against the very serious infection known as methicillin-resistant Staphylococcus aureus (MRSA). Unfortunately, in many hospitals where the antibiotic is prescribed far more freely than before, that’s no longer the case. We now risk losing our last, best hope against the MRSA superbug. “We always try to be one step ahead of the microorganisms,” says Perlin. “But sometimes the microorganisms are one step ahead of us.”