Title

Surprising Alteration of Antibacterial Activity of 5′′-Modified Neomycin against Resistant Bacteria

Document Type

Article

Journal/Book Title

Journal of Medicinal Chemistry

Publication Date

11-14-2008

Publisher

American Chemical Society

Volume

51

Issue

23

First Page

7563

Last Page

7573

DOI

10.1021/jm800997s

Abstract

A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5′′ position has been developed. The structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs.

Comments

PubMed PMID: 19012394; PubMed Central PMCID: PMC2664170

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