Three-Dimensional Solution Structure of Bottromycin A2: A Potent Antibiotic Active against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

School of Pharmacy, Kitasato University, 5–9–1 Shirokane, Minato-ku, Tokyo, Japan.
Chemical & pharmaceutical bulletin (Impact Factor: 1.16). 01/2012; 60(2):169-71. DOI: 10.1248/cpb.60.169
Source: PubMed


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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    • "Mode of action studies revealed the aminoacyl-tRNA binding site (A site) on the 50S ribosome as the target of bottromycins, ultimately leading to the inhibition of protein synthesis (Otaka and Kaji, 1976, 1981, 1983). As this site is currently not addressed by clinically used antibiotics, no crossresistance was observed, and bottromycins are regarded as promising leads to be developed as novel anti-infectives, with renewed interest even in medicinal chemistry (Gouda et al., 2012). Bottromycins represent octapeptides exhibiting an internal tetrapeptide cycle formed via a unique amidine linkage. "
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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 · 6.65 Impact Factor
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    • "The variability of natural compounds with t-butyl group can be illustrated (Fig. 1) by, e.g., pivalic acid or the nonproteinogenic amino acid tert-leucine (Tle). This amino acid was identified, for instance, in teleocidin derivatives, i.e., in blastmycetin E which is produced by the actinomycete Streptoverticillium blastmyceticum (Irie et al. 1990) or in bottromycin A, an antibiotic produced by Streptomyces bottropensis whose structure has been revised at least three times (Gouda et al. 2012). A considerable amount of the pivalic acid, which is found in nature, is assumed to be of anthropogenic origin, e.g., arriving from prodrugs (Brass 2002). "
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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 · 3.34 Impact Factor
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    ABSTRACT: Drug resistant infectious diseases are quickly becoming a global health crisis. While Streptomyces spp. have been a major source of antibiotics over the past 50 years, efficient methods are needed to identify new antibiotics and greatly improve the rate of discovery. LCMS-based metabolomics were applied to analyze extracts of 50 Streptomyes spp. Using this methodology, we discovered bottromycin D and used whole genome sequencing to determine its biosynthesis by a ribosomal pathway.
    Organic Letters 09/2012; 14(19):5050-3. DOI:10.1021/ol3022758 · 6.36 Impact Factor
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