Addendum: Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds.

نویسندگان

  • Yu-Chen Liu
  • Yi-Shan Li
  • Syue-Yi Lyu
  • Li-Jen Hsu
  • Yu-Hou Chen
  • Yu-Ting Huang
  • Hsiu-Chien Chan
  • Chuen-Jiuan Huang
  • Gan-Hong Chen
  • Chia-Cheng Chou
  • Ming-Daw Tsai
  • Tsung-Lin Li
چکیده

In the search for new efficacious antibiotics, biosynthetic engineering offers attractive opportunities to introduce minor alterations to antibiotic structures that may overcome resistance. Dbv29, a flavin-containing oxidase, catalyzes the four-electron oxidation of a vancomycin-like glycopeptide to yield A40926. Structural and biochemical examination of Dbv29 now provides insights into residues that govern flavinylation and activity, protein conformation and reaction mechanism. In particular, the serendipitous discovery of a reaction intermediate in the crystal structure led us to identify an unexpected opportunity to intercept the normal enzyme mechanism at two different points to create new teicoplanin analogs. Using this method, we synthesized families of antibiotic analogs with amidated and aminated lipid chains, some of which showed marked potency and efficacy against multidrug resistant pathogens. This method offers a new strategy for the development of chemical diversity to combat antibacterial resistance.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Determination of teicoplanin concentrations in serum by high-pressure liquid chromatography.

An isocratic reversed-phase high-pressure liquid chromatographic method for the determination of six components of the teicoplanin complex in biological fluid was developed. By using fluorescence detection after precolumn derivatization with fluorescamine, the assay is specific and highly sensitive, with reproducibility studies yielding coefficients of variation ranging from 1.5 to 8.5% (at 5 t...

متن کامل

Teicoplanin metabolism in humans.

Teicoplanin, a lipoglycopeptide antibiotic, consists of five major components (A2-1 through A2-5), one hydrolysis component (A3-1), and four minor components (RS-1 through RS-4). All the major components contain an N-acyl-beta-D-glucosamine, but they differ in the lengths and branchings of their acyl-aliphatic chains. Previous studies with radiolabeled teicoplanin in rats and humans have shown ...

متن کامل

Tailoring of glycopeptide scaffolds by the acyltransferases from the teicoplanin and A-40,926 biosynthetic operons.

The teicoplanin acyltransferase (Atf) responsible for N-acylation of the glucosamine moiety to create the teicoplanin lipoglycopeptide scaffold has recently been identified. Here we use that enzyme (tAtf) and the cognate acyltransferase from the related A-40,926 biosynthetic cluster (aAtf) to evaluate specificity for glycopeptide scaffolds and for the acyl-CoA donor. In addition to acylation of...

متن کامل

Synthesis of New 10-Arylthioanthralins and Oxidation of Thioanthralins to Their Corresponding Sulfones

Treatment of 10-bromoanthralin (1) with several thiophenols (2) gave the corresponding 10-arylthioanthralins (3) in high yields. Oxidation of thioanthralins (3a-c) and (3k-m) using an excess of m-chloroperbenzoic acid gave the corresponding sulfones (4a-c) and (4k-m) in good yields. Oxidation of thioanthralins (3d-f) gave a mixture of the corresponding sulfones (4d-f) and anthralin-10,10'-d...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Nature chemical biology

دوره 11 5  شماره 

صفحات  -

تاریخ انتشار 2011