Abstract
Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Bacterial Agents / biosynthesis
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / isolation & purification
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Anti-Bacterial Agents / pharmacology*
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Betaproteobacteria / chemistry
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Betaproteobacteria / genetics
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Biological Products / chemistry
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Biological Products / isolation & purification
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Biological Products / pharmacology
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Cell Wall / chemistry
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Cell Wall / drug effects
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Cell Wall / metabolism
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Depsipeptides / biosynthesis
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Depsipeptides / chemistry
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Depsipeptides / isolation & purification
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Depsipeptides / pharmacology*
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Disease Models, Animal
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Drug Resistance, Microbial* / genetics
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Female
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Mice
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Microbial Sensitivity Tests
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Microbial Viability / drug effects*
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Molecular Sequence Data
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Multigene Family / genetics
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Mycobacterium tuberculosis / cytology
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / genetics
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Peptidoglycan / biosynthesis
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Staphylococcal Infections / drug therapy
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Staphylococcal Infections / microbiology
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Staphylococcus aureus / chemistry
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Staphylococcus aureus / cytology
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Staphylococcus aureus / drug effects*
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Staphylococcus aureus / genetics
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Teichoic Acids / biosynthesis
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Time Factors
Substances
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Anti-Bacterial Agents
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Biological Products
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Depsipeptides
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Peptidoglycan
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Teichoic Acids
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teixobactin