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Singly Modified Amikacin and Tobramycin Derivatives Show Increased rRNA A‐Site Binding and Higher Potency against Resistant Bacteria
Author(s) -
Fair Richard J.,
McCoy Lisa S.,
Hensler Mary E.,
Aguilar Bernice,
Nizet Victor,
Tor Yitzhak
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402175
Subject(s) - tobramycin , amikacin , cytotoxicity , antibacterial activity , chemistry , pseudomonas aeruginosa , potency , bacteria , escherichia coli , gentamicin , microbiology and biotechnology , antibiotics , biochemistry , in vitro , biology , gene , genetics
Semisynthetic derivatives of the clinically useful aminoglycosides tobramycin and amikacin were prepared by selectively modifying their 6′′ positions with a variety of hydrogen bond donors and acceptors. Their binding to the rRNA A‐site was probed using an in vitro FRET‐based assay, and their antibacterial activities against several resistant strains (e.g., Pseudomonas aeruginosa , Klebsiella pneumonia , MRSA) were quantified by determining minimum inhibitory concentrations (MICs). The most potent derivatives were evaluated for their eukaryotic cytotoxicity. Most analogues displayed higher affinity for the bacterial A‐site than the parent compounds. Although most tobramycin analogues exhibited no improvement in antibacterial activity, several amikacin analogues showed potent and broad‐spectrum antibacterial activity against resistant bacteria. Derivatives tested for eukaryotic cytotoxicity exhibited minimal toxicity, similar to the parent compounds.