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Scientists engineer a powerful new weapon against antibiotic-resistant bacteria

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Gram-negative bacteria like the Klebsiella pneumoniae shown here have an outer membrane that makes them impervious to many drugs, but a new compound from Genentech can breach the border and cripple them.

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Meningitis, pneumonia, deadly diarrhea. Antibiotic developers have long struggled to treat such dreaded diseases because the bacteria that cause them have double cell walls with an outer membrane that is particularly difficult for drugs to penetrate. The only new products to fight such gram-negative bacteria in the past 50 years are variations on existing, already approved drugs. Yet resistance to those classes of compounds is soaring. Now, a team of scientists has created a compound that breaches these bacterial outer membranes in a novel way—and could one day save the lives of people infected with bacteria that today foil every gram-negative antibiotic on the market.

The compound has only been tested against bacteria in lab dishes and in mice so far. Still, the new work is a “tour de force,” says microbiologist Lynn Silver, who for more than 20 years developed antibiotics at Merck and is now a consultant based in Springfield, New Jersey. She calls the compound “a highly promising candidate … against highly antibiotic-resistant pathogens.”

A team led by evolutionary biologist Peter Smith at Genentech, the biotech pioneer in South San Francisco, California, began with a class of natural compounds called arylomycins. Various arylomycins can penetrate the outer membrane of gram-negatives, but they have trouble binding to their target, an enzyme embedded in the inner membrane that juts into the space between the inner and outer walls. So Smith and colleagues chemically modified an arylomycin to “systematically optimize” it such that the drug could more easily reach that space—and bind to the enzyme.

The molecule they created, dubbed G0775, was at least 500 times more potent than a naturally found arylomycin against some of the biggest gram-negative bacterial threats to humans, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. What’s more, it remained potent against all 49 isolates of multidrug-resistant forms of these bacteria that the researchers obtained from patients. In a coup de grâce, when tested against a notoriously drug-resistant strain of K. pneumoniae that has defied 13 different classes of antibiotics, G0775 walloped the bacterium in lab dish experiments, they report today in Nature. “We’re really excited,” Smith says. “We’ve made the necessary changes to the molecules so that they can hit the real deal.”

G0775 also showed in mice it could stymie infections from six strains of four different gram-negative bacteria. It also hasn’t exhibited any potential toxicities in mammalian cells. But the road to antibiotic approval is littered with compounds that later proved toxic in larger animals or during early human trials—or that simply failed to retain their potency.

“It’s a really cool story, but the challenge is going to be for them to push it all the way through, and that’s not an easy thing to do,” says Paul Hergenrother, a chemical biologist at the University of Illinois in Urbana who studies the traits that compounds need to penetrate the outer membranes of gram-negative bacteria.

Hergenrother stresses that, for approval, new antibiotics have to have relatively little toxicity. “With antibiotics, the tolerance for side effects is very low—it’s not like oncology,” he says. But Hergenrother was impressed that the experiments in tests tubes and mice required only modest doses of G0775 to substantially reduce bacterial load. “That’s just what you want to see at this stage of development,” he says.

Hergenrother notes that few antibiotics in the development pipeline are made by experienced drug developers like Genentech, and almost all focus on familiar targets. “The paper signals Genentech’s arrival on the scene as a big player in antibiotics,” he says. “They’ve been in stealth mode, and it’s great to have them.”

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