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.

Amikacin: Uses, Resistance, and Prospects for Inhibition

“…Following these developments, there was a period with relatively few additions to the field of aminoglycosides followed by another period characterized by new approaches that took advantage of the deeper understanding of different aspects of the biology and structure of aminoglycoside modifying enzymes as well as the advances in synthetic chemistry. As a consequence, numerous new generation aminoglycosides, also known as neoglycosides, started to be synthesized [ 19 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. Of the several neoglycosides existing in the pipeline, plazomicin (ACHN-490) ( Figure 2 ), which has been granted Breakthrough Therapy designation by the FDA in May 2017, is the one closest to be approved for human use [ 59 , 60 , 61 , 62 ].…”

Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug-ResistantPseudomonas aeruginosaClinical Isolates

“…23 Our laboratory, and many other research groups, is dedicated to developing AG antibiotics and understanding resistance mechanisms. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Previously, researchers have observed discrepant results over whether AG and carbapenem combination therapies yield positive outcomes for the killing of P. aeruginosa. [40][41][42][43] In an effort to understand in greater detail the underlying resistance mechanisms in P. aeruginosa, in this study, we obtained 122 multidrug-resistant P. aeruginosa clinical isolates from the University of Kentucky Hospital System and evaluated the in vitro activity of various clinically relevant AGs, including AMK, APR, GEN, NET, SIS, and TOB, and two carbapenem antibiotics, meropenem (MEM) and imipenem (IPM), against these clinical isolates.…”

Highly selective acylation of polyamines and aminoglycosides by 5-acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-ones

“… 28 , 29 Moreover, those methods afforded pure products in only 20–40% isolated yields. Although modern methods for acylation of 6′-position of kanamycin, tobramycin and amikacin as sulfate salts using N -hydroxysuccinymyl (NHS) esters have been reported 30 with yields up to 91%, the scope of this methodology is limited to substituted acetyl derivatives. Selective introduction of acetyl groups into aminoglycosides using chemoenzymatic methods 31 or RNA-based aptameric groups 13 have been also reported.…”