Teixobactin: Powerful New Antibiotic Kills Drug-Resistant Bacteria

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A group of researchers led by Prof Kim Lewis of Northeastern University in Boston, Massachusetts, has discovered a new antibiotic that eliminatesMethicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis, Streptococcus pneumoniae, Bacillus anthracis and other dangerous pathogens without encountering any detectable resistance.

Teixobactin’s discovery presents a promising new opportunity to treat chronic infections caused by MSRA that is highly resistant to antibiotics, as well as tuberculosis, which involves a combination of therapies with negative side effects,” Prof Lewis said.

“Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s.” Prof Lewis and his colleagues spent years seeking to address this problem by tapping into a new source of antibiotics beyond those created by synthetic means: uncultured bacteria, which make up 99 percent of all species in external environments.

They developed a novel method for growing uncultured bacteria in their natural environment, which led to the founding of NovoBiotic Pharmaceuticals in Cambridge, Massachusetts.

Their approach involves the iChip, a miniature device that can isolate and help grow single cells in their natural environment and thereby provides researchers with much improved access to uncultured bacteria.

“NovoBiotic has since assembled about 50,000 strains of uncultured bacteria and discovered 25 new antibiotics, of which teixobactin is the latest and most interesting,” said Prof Lewis, who is the senior author of the paper published in the journal Nature.

Teixobactin was discovered during a routine screening for antimicrobial material using this method.

The scientists then tested the compound for resistance development and did not obtain any mutants of MSRA or Mycobacterium tuberculosis resistant to it.

“Our impression is that nature produced a compound that evolved to be free of resistance,” Prof Lewis said.

Model for the mechanism of action of teixobactin: lipid II, precursor of peptidoglycan, is synthesized in the cytoplasm and flipped to the surface of the inner membrane by MurJ or FtsW; lipid III, a precursor of wall teichoic acid (WTA), is similarly formed inside the cell and WTA lipid-bound precursors are translocated across the cytoplasmic membrane by the ABC-transporter TarGH. Teixobactin (TEIX) forms a stoichiometric complex with cell wall precursors, lipid II and lipid III. Abduction of these building blocks simultaneously interrupts peptidoglycan (right), WTA (left) biosynthesis as well as precursor recycling. Binding to multiple targets within the cell wall pathways obstructs the formation of a functional cell envelope. The producer of teixobactin is a gramnegative bacterium which is protected from this compound by exporting it outside of its outer membrane permeability barrier; the target gram-positive organisms do not have an outer membrane. CM – cytoplasmic membrane; CW – cell wall; OM – outer membrane; LTA – lipoteichoic acid; WTA – wall teichoic acid. Image credit: Losee L. Ling et al.

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