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Synthesis of saccharocin from apramycin and evaluation of its ribosomal selectivity.

ABSTRACT: We describe a straightforward synthesis of the apramycin biosynthetic precursor saccharocin from apramycin by regioselective partial azidation followed by stereoretentive oxidative deamination. Saccharocin was found to exhibit excellent selectivity for inhibition of the bacterial ribosome over the eukaryotic ribosomes indicating that its presence as a minor impurity in apramycin itself should not be problematic in the development of the latter as a clinical candidate.

SUBMITTER: Sarpe VA

PROVIDER: S-EPMC6482888 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Synthesis of saccharocin from apramycin and evaluation of its ribosomal selectivity.

Sarpe Vikram A VA Pirrone Michael G MG Haldimann Klara K Hobbie Sven N SN Vasella Andrea A Crich David D

MedChemComm 20190313 4

We describe a straightforward synthesis of the apramycin biosynthetic precursor saccharocin from apramycin by regioselective partial azidation followed by stereoretentive oxidative deamination. Saccharocin was found to exhibit excellent selectivity for inhibition of the bacterial ribosome over the eukaryotic ribosomes indicating that its presence as a minor impurity in apramycin itself should not be problematic in the development of the latter as a clinical candidate. ...[more]

PMID: 31057735

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Project description:Apramycin is a structurally unique member of the 2-deoxystreptamine class of aminoglycoside antibiotics characterized by a monosubstituted 2-deoxystreptamine ring that carries an unusual bicyclic eight-carbon dialdose moiety. Because of its unusual structure, apramycin is not susceptible to the most prevalent mechanisms of aminoglycoside resistance including the aminoglycoside-modifying enzymes and the ribosomal methyltransferases whose widespread presence severely compromises all aminoglycosides in current clinical practice. These attributes coupled with minimal ototoxocity in animal models combine to make apramycin an excellent starting point for the development of next-generation aminoglycoside antibiotics for the treatment of multidrug-resistant bacterial infections, particularly the ESKAPE pathogens. With this in mind, we describe the design, synthesis, and evaluation of three series of apramycin derivatives, all functionalized at the 5-position, with the goals of increasing the antibacterial potency without sacrificing selectivity between bacterial and eukaryotic ribosomes and of overcoming the rare aminoglycoside acetyltransferase (3)-IV class of aminoglycoside-modifying enzymes that constitutes the only documented mechanism of antimicrobial resistance to apramycin. We show that several apramycin-5-O-β-d-ribofuranosides, 5-O-β-d-eryrthofuranosides, and even simple 5-O-aminoalkyl ethers are effective in this respect through the use of cell-free translation assays with wild-type bacterial and humanized bacterial ribosomes and of extensive antibacterial assays with wild-type and resistant Gram negative bacteria carrying either single or multiple resistance determinants. Ex vivo studies with mouse cochlear explants confirm the low levels of ototoxicity predicted on the basis of selectivity at the target level, while the mouse thigh infection model was used to demonstrate the superiority of an apramycin-5-O-glycoside in reducing the bacterial burden in vivo.

Dataset Information

Synthesis of saccharocin from apramycin and evaluation of its ribosomal selectivity.

Publications

Synthesis of saccharocin from apramycin and evaluation of its ribosomal selectivity.

Similar Datasets

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