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Biological Chemistry

Novel Bacteria Fighter Unearthed

Antibiotics: Uncultured bacteria yield teixobactin, a pathogen killer which evades detectable resistance

by Bethany Halford
January 8, 2015 | APPEARED IN VOLUME 93, ISSUE 2

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 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 pneumoniae 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 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 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 multi-drug-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.



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Brilacidin 101 (January 11, 2015 1:55 PM)
Lots of PR surrounding it, but some reason to stem the enthusiasm, at least for now. The com­pound is at least 4-5 years behind another sim­ilar antibi­otic that I haven’t seen get the atten­tion it deserves. The one I’m talking about just fin­ished Phase 2B trials for ABSSSI and was granted QIDP status under the GAIN act here across the pond in America. In the ABSSSI study results matched or sur­pass Daptomycin’s 7 day treat­ment either as a 3 day or as a 1 day course of treat­ment. Even better, testing indi­cates that bac­te­rial resis­tance is extremely unlikely to develop (check out the clinical data below in the Slide Deck).
The com­pany is Cell­ceutix, and one of their leading drugs in devel­op­ment, Brilacidin, also attacks the bac­teria cell walls. Right now, it’s going into Phase 3 for severe skin infec­tions, such as MRSA and other resis­tant super­bugs, including ***Gram negative bacteria. It’s part of a new class (a true new class) of antibi­otics called Defensin Mimetics. Bac­teria would need to evolve an entire new cell wall struc­ture to develop immu­nity, sim­i­larly to Teixobactin, only, again, this drug is a lot fur­ther along in the approval process. You can Google it and check out some of the company’s press releases, including pub­lished results. This introduction is just the tip of the iceberg.
Cellceutic acquired Polymedix Assets in 2013
Comparative Mechanistic Studies of Brilacidin, Daptomycin and the Antimicrobial Peptide LL1

Read more:
Daniel Nielsen (February 4, 2015 7:21 PM)
Why is this categorised as a small-molecule on the "ACS molecule of the week"? The only other place where "small-molecule" is used in the context of Teixoban is on Wikipedia. The 2015 Nature publication describes the structure as "an unusual depsipeptide".
Clearly this is not a small molecule.

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