Three-dimensional solution structure of bottromycin A2: a potent antibiotic active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci.
ABSTRACT The three-dimensional (3D) structure of bottromycin A(2), a natural anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-vancomycin-resistant Enterococci (VRE) agent consisting of seven amino acids, has been investigated through NMR spectroscopy. On the basis of 57 experimental constraints, a total of 34 converged structures were obtained. The average pairwise atomic root mean square difference is 0.74±0.59 Å for all heavy atoms. The resulting structure indicates an interesting feature in that the three C-terminal residues of bottromycin A(2) fold back on the 12-membered cyclic skeleton made by the four N-terminal residues. Thus, MePro(2) and Thia-β-Ala-OMe(7), modification of which significantly affects the antibacterial activities of bottromycin A(2), are located on one side of its 3D structure. These distinct structural features might be important for the binding of bottromycin A(2) with the bacterial ribosome.
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ABSTRACT: Bottromycins represent a promising class of antibiotics binding to the therapeutically unexploited A-site of the bacterial ribosome. By inhibiting translation they are active against clinically important pathogens, such as vancomycin-resistant Enterococci. Structurally, bottromycins are heavily modified peptides exhibiting various unusual biosynthetic features. To set the stage for compound modification and yield optimization, we identified the biosynthetic gene cluster, used synthetic biotechnology approaches to establish and improve heterologous production, and generated analogs by pathway genetic engineering. We unambiguously identified three radical SAM methyltransferase-encoding genes required for various methylations at unactivated carbons yielding tert-butyl valine, methyl-proline, and β-methyl-phenylalanine residues, plus a gene involved in aspartate methyl-ester formation. Evidence for the formation of the exo-thiazole unit and for a macrocyclodehydration mechanism leading to amidine ring formation is provided.Chemistry & biology 09/2012; 19(10):1278-1287. DOI:10.1016/j.chembiol.2012.08.013
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ABSTRACT: Occurrence, biosynthesis, and biodegradation of pivalic acid and other compounds, having a quaternary carbon atom by different bacteria, are described. We have summarized the relevant data that have so far been published, presenting them in a graphical form, i.e., as biodegradation pathways including B₁₂-dependent isomerization and desaturation that lead to the degradation of pivalic acid and similar compounds to products with other than quaternary carbon atoms, i.e., compounds whose catabolism is well known.Applied Microbiology and Biotechnology 07/2012; 95(6):1371-6. DOI:10.1007/s00253-012-4267-x
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ABSTRACT: Thio-Ugi reactions are described as an excellent synthetic tool for the synthesis of sterically highly hindered endothiopeptides. S-Methylation and subsequent amidine formation can be carried out in an inter- as well as in an intramolecular fashion. The intramolecular approach allows the synthesis of the bottromycin ring system in a straightforward manner.Beilstein Journal of Organic Chemistry 01/2012; 8:1652-6. DOI:10.3762/bjoc.8.189