The War on Superbugs
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It’s a painstaking process that typically begins with large-scale, random screening of microorganism-filled solutions made from soils dug up around the world. The solutions are applied to lab plates containing disease-causing bacteria to gauge which may be effective. Each strain takes months to purify, and of the few that show antibacterial ability, many won’t prove safe for humans, at least by the FDA’s increasingly stringent standards. “If you discovered penicillin today, it would never get to market,” Wright says. “Some people are allergic to penicillin and have an anaphylactic reaction that could be fatal. Unless you’ve got nothing else, it gets harder and harder to make new drugs.”
That situation begs for fresh approaches, and scientists at Merck Research Laboratories in Rahway, N.J., have been trying a variation on the traditional method, which tends to turn up the same antibiotics that kill bacteria in the same way (that have the same problems with resistance). By searching for a specific type of hypothetical antibiotic—one that, for example, halts the production of fatty acids essential to the membranes that encapsulate the bacteria—they could, in theory, avoid sorting through already-discovered compounds.
The scientists have seeded lab plates with S. aureus genetically engineered to have low levels of a protein called FabF, which helps synthesize fatty acids. That makes this version of the pathogen 50 times more sensitive to any antibiotic that targets the bacteria’s fatty acids. So although normal S. aureus bacteria with high levels of FabF might survive an assault—as they have, during previous screenings—creating the ultrasensitive bacteria could help the scientists isolate an antibiotic that works against the staph and could take on the full-strength pathogen.
After screening 83,000 natural products at three concentrations from soils, the Merck scientists finally found a substance from South Africa that killed the sensitized staph. That compound, which they named platensimycin, inhibits FabF. When used to treat mice infected with staph, it eradicated the bacteria. It also worked against many other types of infection, and the company may begin clinical trials.
Scientists at several laboratories have discovered additional compounds that act against other novel bacterial targets, such as cell division. And researchers at the Scripps Institution of Oceanography in La Jolla are now screening strains of bacteria from the ocean bottom to see whether they might be of use. But the problem with platensimycin and the rest of these potential drugs is that they’re all still traditional antibiotics, and bacteria will eventually develop resistance to them. Attacking virulence factors, which researchers have been investigating since the 1980s, could prove more effective.
Under the microscope, Staphylococcus aureus is a pleasing shade of gold (aureus means golden) thanks to a pigment called staphyloxanthin, which is similar in structure to carotenoids, the colorful antioxidants found in many fruits and vegetables. In their work on staph, Victor Nizet, at the University of California, San Diego, and George Liu, now at Cedars-Sinai Medical Center and UCLA, discovered that staphyloxanthin is also partly responsible for the bacterium’s virulence. The antioxidant shield that the pigment provides seems to protect the bug from the oxidants that the body’s white blood cells use to destroy bacteria. In fact, Nizet discovered that when his laboratory used genetic techniques to remove the golden pigment from the staph, the mice no longer got sick.
Upon reading Nizet and Liu’s work, Eric Oldfield, a chemist at the University of Illinois at Urbana-Champaign, realized that staphyloxanthin formation in bacteria looks chemically similar to early cholesterol formation in humans. He wondered whether cholesterol drugs could prevent the synthesis of staphyloxanthin. Oldfield contacted Nizet, and, with a few other specialists, tried out several cholesterol drugs. One, BPH-652, did a wonderful job of preventing staph from becoming golden, thus allowing a mouse’s immune system to kill the bacteria. Previously, clinical trials of BPH-652 for fighting cholesterol stalled after failing to work as well as statins. Soon Nizet hopes to add the drug to the antibacterial arsenal.
Yet even if BPH-652 succeeds as a magic bullet against MRSA, that’s just one of many increasingly drug-resistant bacteria. “The problem with antivirulence is it’s very targeted, and just knocking out a single virulence factor in a single organism may not be very cost effective,” says Hancock of the University of British Columbia. Still, given how huge a problem drug resistance has become, even an expensive, narrow fix may be better than nothing. Stuart Levy, an antibiotic resistance expert at Tufts University, calls work with virulence factors “the way of the future.” He is leading a symposium on antivirulence strategies at the Interscience Conference on Antimicrobial Agents and Chemotherapy in October.
