Aminoglycoside antibiotics: old drugs and new therapeutic approaches

Abstract

Aminoglycoside antibiotics kill bacteria by binding to the ribosomal decoding site and reducing fidelity of protein synthesis. Since the discovery of these natural products over 50 years ago, aminoglycosides have provided a mainstay of antibacterial therapy of serious Gram-negative infections. In recent years, aminoglycosides have become important tools to study molecular recognition of ribonucleic acid (RNA). In an ingenious exploitation of the aminoglycosides' mechanism of action, it has been speculated that drug-induced readthrough of premature stop codons in mutated messenger RNAs might be used to treat patients suffering from certain heritable genetic disorders.

Synthesis and Spectrum of the Neoglycoside ACHN-490

“…Numerous such enzymes have been identified, and they often occur in combinations that can impart broad AG resistance (15). Less common AG resistance mechanisms (AGRMs) among the Enterobacteriaceae involve the regulation of intracellular drug concentration by overexpression of efflux pumps and the expression of enzymes that modify the ribosomal target (10). As broad-spectrum antibiotics, including the existing AGs cephalosporins, carbapenems, and fluoroquinolones, are rendered ineffective by increasing resistance, new AGs are an attractive option for the treatment of serious infections, especially if developed with optimized dosing regimens to maximize safety and efficacy (7).…”

Structure-Activity Relationships among the Kanamycin Aminoglycosides: Role of Ring I Hydroxyl and Amino Groups

“…Aminoglycosides are inactivated by N-acetylation because two effects occur in parallel: loss of a functional interaction, i.e., an important hydrogen bond provided by the charged amino group, and steric hindrance due to the introduction of the acetyl group. There is renewed interest in aminoglycosides (19), mainly as a consequence of two recent developments: (i) the availability of crystal structures revealing breathtaking details of drug-target interaction (9,13,39) and (ii) the advance in genetic manipulations allowing unprecedented precision in functional studies of drugtarget interaction (2,15,36). Here, we investigated the contributions of subtle variations of ring I substituents to drug activity by focusing on kanamycin derivatives with different 2=, 3=, 4=, and 6= substituents.…”

Mapping Targetable Sites on Human Telomerase RNA Pseudoknot/Template Domain Using 2′-OMe RNA-interacting Polynucleotide (RIPtide) Microarrays

“…The realization that the majority of proteins are considered intractable toward targeting by established agents has fueled efforts to develop the therapeutic potential of alternative classes of cellular targets, with RNA being the object of most intensive investigation (2,3). Although examples are known of small molecules that target RNA potently and specifically (3)(4)(5), most efforts have taken advantage of the fact that nucleic acids target each other efficiently and selectively through nucleobase-pairing interactions (2). This mode of intermolecular engagement requires that the target sequence be minimally tied up in competing intramolecular base-pairing interactions.…”

“…Microarrays representing all possible ligand sequences would serve the valuable function of providing a more unbiased and comprehensive approach, but these have not been available to date. With the relatively long sequences (Ͼ15 nt 6 ) of unmodified DNA oligonucleotides typically required to form a stable Watson-Crick pairing with RNA targets, the total number of candidate sequences (4 n , where n equals the number of nucleobases in the oligonucleotide) greatly exceeds the capacity of even the highest density microarrays presently available. The use of nucleoside analogs can boost target affinity, thereby reducing the length of the candidate ligands and hence overall library size, but the use of such analogs requires the development of dedicated methods for fabrication for high density microarrays.…”