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Issue 11, 2011
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Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance

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Abstract

Amongst the many synthetic aminoglycoside analogues that were developed to regain the efficacy of this class of antibiotics against resistant bacterial strains, the 1-N-acylated analogues are the most clinically used. In this study we demonstrate that 6′-N-acylation of the clinically used compound tobramycin and 6′′′-N-acylation of paromomycin result in derivatives resistant to deactivation by 6′-aminoglycoside acetyltransferase (AAC(6′)) which is widely found in aminoglycoside resistant bacteria. When tested against AAC(6′)- or AAC(3)-expressing bacteria as well as pathogenic bacterial strains, some of the analogues demonstrated improved antibacterial activity compared to their parent antibiotics. Improvement of the biological performance of the N-acylated analogues was found to be highly dependent on the specific aminoglycoside and acyl group. Our study indicates that as for 1-N-acylation, 6′- and 6′′′-N-acylation of aminoglycosides offer an additional promising direction in the search for aminoglycosides capable of overcoming infections by resistant bacteria.

Graphical abstract: Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance

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Publication details

The article was received on 07 Dec 2010, accepted on 27 Jan 2011 and first published on 28 Jan 2011


Article type: Paper
DOI: 10.1039/C0OB01133A
Citation: Org. Biomol. Chem., 2011,9, 4057-4063
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    Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance

    P. Shaul, K. D. Green, R. Rutenberg, M. Kramer, Y. Berkov-Zrihen, E. Breiner-Goldstein, S. Garneau-Tsodikova and M. Fridman, Org. Biomol. Chem., 2011, 9, 4057
    DOI: 10.1039/C0OB01133A

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