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Synthesis of a Pseudodisaccharide Suitable for Synthesis of Ring I Modified 4,5-2-Deoxystreptamine Type Aminoglycoside Antibiotics.

ABSTRACT: To facilitate the synthesis of paromomycin and/or neomycin analogues, we describe a cleavage of ring I from paromomycin that proceeds in the presence of azides and affords a glycosyl acceptor for the installation of a modified ring I. A paromomycin 4',6'-diol is oxidized by the Dess-Martin periodinane followed by m-chloroperoxybenzoic acid. Base treatment then affords a protected pseudodisaccharide, which functions as a glycosyl acceptor. The method should also apply to the cleavage of pyranosyl 4,6-diols from oligosaccharides and glycoconjugates.

SUBMITTER: Sonousi A

PROVIDER: S-EPMC7275914 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Synthesis of a Pseudodisaccharide Suitable for Synthesis of Ring I Modified 4,5-2-Deoxystreptamine Type Aminoglycoside Antibiotics.

Sonousi Amr A Vasella Andrea A Crich David D

The Journal of organic chemistry 20200508 11

To facilitate the synthesis of paromomycin and/or neomycin analogues, we describe a cleavage of ring I from paromomycin that proceeds in the presence of azides and affords a glycosyl acceptor for the installation of a modified ring I. A paromomycin 4',6'-diol is oxidized by the Dess-Martin periodinane followed by <i>m</i>-chloroperoxybenzoic acid. Base treatment then affords a protected pseudodisaccharide, which functions as a glycosyl acceptor. The method should also apply to the cleavage of py ...[more]

PMID: 32336094

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Project description:Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-negative infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or rRNA methyl transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quantitative ribosome footprinting, and X-ray crystallography support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.

Dataset Information

Synthesis of a Pseudodisaccharide Suitable for Synthesis of Ring I Modified 4,5-2-Deoxystreptamine Type Aminoglycoside Antibiotics.

Publications

Synthesis of a Pseudodisaccharide Suitable for Synthesis of Ring I Modified 4,5-2-Deoxystreptamine Type Aminoglycoside Antibiotics.

Similar Datasets

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