An antibacterial compound with a novel structure and mechanism of action has been identified, isolated, and tested in mice. If the compound, known as teixobactin, makes it successfully through clinical trials, it will represent the first new class of antibiotic to be discovered in a decade.
“Most of the antibiotics we have in our drugstores and clinics have been isolated from soil microorganisms,” explains Kim Lewis, a biology professor at Boston’s Northeastern University who led the research effort. “But only about 1% of environmental microorganisms will grow on petri dishes in the lab. The rest are unculturable.” Using a novel screening method that coaxes such unculturable bacteria to grow, Lewis and his colleagues were able to unearth teixobactin (Nature 2015, DOI: 10.1038/nature14098).
In cell-based tests, teixobactin was able to kill many types of gram-positive pathogens, including drug-resistant strains. Tests in mice showed the compound was effective against methicillin-resistant Staphylococcus aureus and Streptococcus pneumonia with low toxicity.
Furthermore, the researchers were unable to grow mutants of either S. aureus or Mycobacterium tuberculosis that were resistant to teixobactin. The researchers believe that teixobactin’s novel mechanism of action accounts for its resistance-defying ability. The compound doesn’t target proteins, which readily evolve to produce resistance. Rather, teixobactin binds to the pyrophosphate-sugar moiety of cell envelope precursors that are readily accessible on the outside of gram-positive bacteria. There it mucks up the bacteria’s ability to build their cell walls.
Developing the method to find and grow soil microorganisms that are the source for teixobactin was equally pathbreaking. “The idea for growing uncultured bacteria is very simple,” Lewis says. Because these bacteria grow in their natural environment—soil—the researchers figured they’d use soil to make them flourish in the lab. The key is a gadget called the iChip—a tiny diffusion chamber with many tiny channels. Soil samples are diluted so that approximately one bacterial cell is in each channel. Then the gadget is sandwiched between two semipermeable membranes and buried in the soil for a week or two.
“Essentially we’re tricking the bacteria, and they don’t know something happened to them,” Lewis notes. “They start growing and form colonies. Once they’ve formed colonies, there’s a high probability they will be able to grow on regular petri dishes. Once that happens, they become domesticated.”
Then, the researchers screen the bacterial colonies for their ability to kill pathogens, such as S. aureus. When they find a hit, they will isolate and identify the antibacterial compound involved. Using this method, the researchers screened 10,000 bacterial isolates for antibacterial activity and identified 25 potential new antibiotics, of which teixobactin was the most promising.
“It’s exciting to see a novel antibiotic that is effective against multidrug-resistant gram-positive bacteria, with a different mechanism of action from known anti-infective agents,” comments Karen Bush, a biochemist at Indiana University, Bloomington, who worked on antibiotics in the pharmaceutical industry for more than 30 years. Bush cautions that despite the report’s claims, bacteria could still develop resistance to teixobactin. “Bacteria have been clever enough to develop resistance to every other antibiotic. There is no obvious reason why this will not occur with teixobactin,” she points out.
Even so, Lewis notes that the discovery of compounds such as teixobactin suggests that uncultured bacteria are “a promising source in general for antibiotics and have the chance of helping revive the field of antibiotic discovery.” He speculates that teixobactin could be in clinical trials within two years.