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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Depsipeptides/pharmacology , Drug Resistance, Microbial , Microbial Viability/drug effects , Mycobacterium tuberculosis/drug effects , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Betaproteobacteria/chemistry , Betaproteobacteria/genetics , Biological Products/chemistry , Biological Products/isolation & purification , Biological Products/pharmacology , Cell Wall/chemistry , Cell Wall/drug effects , Cell Wall/metabolism , Depsipeptides/biosynthesis , Depsipeptides/chemistry , Depsipeptides/isolation & purification , Disease Models, Animal , Drug Resistance, Microbial/genetics , Female , Mice , Microbial Sensitivity Tests , Molecular Sequence Data , Multigene Family/genetics , Mycobacterium tuberculosis/cytology , Mycobacterium tuberculosis/genetics , Peptidoglycan/biosynthesis , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/chemistry , Staphylococcus aureus/cytology , Staphylococcus aureus/genetics , Teichoic Acids/biosynthesis , Time FactorsABSTRACT
A new isofuranonaphthoquinone, 7,8-dihydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione, was isolated from cultures of an Actinoplanes isolate obtained using an in situ diffusion technology that facilitates the isolation of soil microorganisms. This compound was demonstrated to have the ability to complex Fe(III). The structure was determined on the basis of spectroscopic data.
Subject(s)
Actinomycetales/chemistry , Furans/isolation & purification , Naphthoquinones/isolation & purification , Furans/chemistry , Iron/chemistry , Iron/metabolism , Molecular Structure , Naphthoquinones/chemistry , Nuclear Magnetic Resonance, Biomolecular , Soil MicrobiologyABSTRACT
Two novel antibiotics, neocitreamicins I and II, were isolated from a fermentation broth of a Nocardia strain. This producing strain was obtained using an in situ diffusion chamber that facilitates the cultivation of soil microorganisms. The structures of neocitreamicins I and II were elucidated using UV, MS, and NMR data, and found to be related to the polycyclic xanthone antibiotics of the citreamicin class. The neocitreamicins showed in vitro activity against Gram-positive bacteria including strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Enterococcus/drug effects , Methicillin Resistance , Oxazoles/isolation & purification , Oxazoles/pharmacology , Staphylococcus aureus/drug effects , Vancomycin Resistance , Anti-Bacterial Agents/chemistry , Culture Media/chemistry , Mass Spectrometry , Nocardia/growth & development , Nocardia/isolation & purification , Nocardia/metabolism , Oxazoles/chemistry , Soil Microbiology , Spectrum AnalysisABSTRACT
A screening campaign was implemented utilizing capillary electrophoresis as a primary assay to discover binders to the cancer target Akt1 from a crude natural extract library. Fungal extracts with binding activities were characterized for biochemical inhibition of Akt1 to phosphorylate the downstream substrate protein Bad. One of the crude extracts with bioactivity selected for isolation and structure elucidation from fermentation of the fungal culture Oidiodendron sp. F01895 yielded a new trihydroxy phthalide (1). The structure of 1 was determined by a combination of 1D and 2D NMR spectroscopic data along with high-resolution mass spectrometric data. Compound 1 displays inhibition of Akt1 biochemical activity in vitro and confers growth inhibition on some cancer-derived cell lines in culture.
