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Issue 1, 2016
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Drug-target networks in aminoglycoside resistance: hierarchy of priority in structural drug design

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Abstract

Antibiotic resistance is a multifactorial problem that demands multifaceted strategies to address. Here we present a drug-target network analysis of the clinically most prominent mechanism of resistance to aminoglycoside antibiotics, i.e. enzyme mediated modification of the antibiotics. This drug-target network displays prominent resistance preferences for 4,6-disubstituted aminoglycosides such as tobramycin and gentamicin, reflective of their extensive clinical usage. Further analysis also highlights aminoglycosides that remain more resilient to modifications by various bacterial resistance enzymes. This aminoglycoside resistance drug-target network conveys a compelling case for prioritization of next-generation aminoglycosides development exploiting 4,5-disubstituted and non-deoxystreptamine aminoglycoside scaffolds to surmount rising drug-resistance, in conjunction with advancing inhibitor/adjuvant leads effective against multiple aminoglycoside modifying enzyme.

Graphical abstract: Drug-target networks in aminoglycoside resistance: hierarchy of priority in structural drug design

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Supplementary files

Article information


Submitted
05 Sep 2015
Accepted
09 Dec 2015
First published
10 Dec 2015

Med. Chem. Commun., 2016,7, 103-113
Article type
Review Article

Drug-target networks in aminoglycoside resistance: hierarchy of priority in structural drug design

V. R. Bacot-Davis, A. V. Bassenden and A. M. Berghuis, Med. Chem. Commun., 2016, 7, 103
DOI: 10.1039/C5MD00384A

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