The War on Superbugs
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Brent Humphreys for Proto
Bacteria are everywhere—in the soil and air, on our skin and in our food. On a typical day we may be exposed to millions of them. Most of the time they don’t make us sick, largely because of the multilayered defenses of the innate immune system. At its simplest level, innate immunity consists of a barrier of skin or mucus that prevents infectious agents from getting inside the body. If a pathogen does get through, innate immunity follows up with a complex system of cells and proteins that attack foreign intruders. But innate immunity can’t stop all bacteria, and scientists have long wondered how the system might be enhanced. In one approach, they have tried stimulating cell proteins known as toll-like receptors, which normally trigger an immune response. But artificially activating those receptors can promote sepsis, a raging inflammatory response that causes 200,000 deaths a year.
In looking for a way to ramp up innate immunity without sepsis, Hancock has studied peptides, small proteins that serve, with the rest of the innate immune system, as a quick, first-line defense against invading bacteria. (The adaptive immune system—antibodies and the like—takes days to ramp up and kill invading pathogens.) Hancock found he could engineer peptides that promote the bacteria-killing parts of the innate immune system without also igniting the body’s sometimes-dangerous inflammatory response. In 2002 he created a peptide called IDR-1 that, given to mice during a window from 48 hours before an MRSA infection to six hours afterward, prevented or treated the infection without sepsis or allergic reaction. What’s more, Hancock thinks that IDR-1 could be used to re-energize traditional antibiotics to which bacteria have become resistant. In work with animals, IDR-1 has greatly improved the performance of antibiotics that were losing effectiveness. If it works in humans, one possible application would be to give it to people entering the hospital to help them avoid common infections.
Hancock considers this approach a natural way to combat bacteria. “I think we often arrogantly feel we can trump evolution,” he says. “But with antibiotics, we tried to overextend a particular weapon. For every weapon in nature there’s a counterweapon—antibiotic resistance, in this case. But with innate immunity, you’re using a response worked out by evolutionary forces. It can be very effective.”
Enhancing innate immunity, disabling virulence factors and attacking bacteria by interfering with fatty acid production or other essential processes all hold promise, as does targeting antibiotic resistance directly. One drug already on the market, Augmentin, contains amoxicillin and clavulanate potassium, a beta-lactamase inhibitor. (Beta-lactamase is an enzyme that bacteria use to destroy the amoxicillin; by inhibiting it, the antibiotic can still be effective.) Other research is focused on efflux pumps, transport proteins that churn antibiotics back out as soon as they enter. Eliminating the pumps might return power to older antibiotics. Still other scientists are working to prevent bacterial biofilms, colonies of bacteria that are all but impossible to eradicate.
Yet despite the excitement surrounding these approaches, most of the potential new drugs are far from clinical use. “We are still in a crisis period,” says Tuft’s Levy. “Most of the large pharmaceutical companies have left the drug-discovery field. And with bacteria becoming resistant to multiple drugs, it’s hard to know which antibiotic to use. People are dying from resistant infections every day.”
