title: Synthesis and Biological Activity of Mono- and Di-N-acylated Aminoglycosides.
abstract: Despite issues with oto/nephrotoxicity and bacterial resistance, aminoglycosides (AGs) remain an effective and widely used class of antibacterial agents. For decades now, efforts toward the development of novel AGs with potential to overcome some of these problems have been major research focuses. 1-N-Acylation, especially γ-amino-β-hydroxybutyrate (AHB) derivatization, has proven to be one of the most successful strategies for improving the overall properties of AGs, including their ability to avoid certain resistance mechanisms. More recently, 6'-N-acylation arose as another possible strategy to improve the properties of these drugs. In this study, we report on the glycinyl, carboxybenzyl, and AHB mono- and diderivatization at the 1-, 6'-, and/or 4‴-amines of the AGs amikacin, kanamycin A, netilmicin, sisomicin, and tobramycin. We also present the antibacterial activities and the reduced reactivity of AG-modifying enzymes (AMEs) toward these new AG derivatives, and identify the AMEs present in the bacterial strains tested.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
authors.forename: Nishad
authors.initials: N
authors.lastname: Thamban Chandrika
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: Department of Medicinal Chemistry and Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Houghton
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
keywords: Acylation; aminoglycoside antibiotics; bacterial resistance; drug development; drug-modifying enzymes