Scientists engineer a powerful new weapon against antibiotic-resistant bacteria | Science

Meningitis, pneumonia, deadly diarrhea. Antibiotic developers have long struggled to treat such dreaded diseases because they 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 new way and can save the lives of people infected with antibiotics on the market.

The compound has been tested against bacteria Still, the new work is a "tour de force," says Lynn Silver's microbiologist, who is more than 20 years old 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."

Peter Smith at Genentech, the biotech pioneer in South San Francisco, California, started with a class of natural compounds called arylomycins. Various arylomycins can penetrate the outer membrane of gram-negative, 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 so 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 Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. What's more, it remains potent against all the isolates of multidrug-resistant forms of these bacteria that the patients obtained from. In a coup de grace, when tested against a notoriously drug-resistant strain of K. pneumoniae that has defied 13 different classs of antibiotics, G0775 walloped the bacteria 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 has not exhibited any potential toxicities in mammalian cells. But the road to antibiotic approval has been proven to be more or less effective in the early stages of clinical trials, or simply failed to retain their potency.

"It's a really cool story," says Paul Hergenrother, a chemical biologist at the University of Illinois in Urbana who studies, "but it's a really cool story, but the challenge is going to be pushing it all the way through," says Paul Hergenrother. the features that compounds need to penetrate the outer membranes of gram-negative bacteria.

Hergenrother stresses that, for approval, new antibiotics. "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 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 fashion, and it's great to have them."