N6′, N6′′′, and O4′ Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity

Sati, Girish C.; Shcherbakov, Dimitri; Hobbie, Sven N.; Vasella, Andrea; Böttger, Erik C.; Crich, David

doi:10.1021/acsinfecdis.6b00214

Cited by 15 publications

(22 citation statements)

References 77 publications

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“…While ring IV's features in the current map are weaker relative to those of rings I-III, we were able to identify interactions of ring IV with surrounding 16S rRNA nucleotides and ordered solvent molecules that were not previously modeled. Importantly, the observed interactions between the N6''' amino group and the phosphate backbone of nucleotides G1489-U1490 in particular are likely responsible for known susceptibility of PAR to N6''' modification (Sati et al, 2017). While the same loss of interactions is expected for neomycin, which differs from paromomycin only by the presence of a 6'-hydroxy rather than a 6'-amine in ring I, the penalty of modifying N6''' in neomycin is likely compensated for by the extra positive charge and stronger hydrogen bonding observed with neomycin ring I (Sati et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the observed interactions between the N6''' amino group and the phosphate backbone of nucleotides G1489-U1490 in particular are likely responsible for known susceptibility of PAR to N6''' modification (Sati et al, 2017). While the same loss of interactions is expected for neomycin, which differs from paromomycin only by the presence of a 6'-hydroxy rather than a 6'-amine in ring I, the penalty of modifying N6''' in neomycin is likely compensated for by the extra positive charge and stronger hydrogen bonding observed with neomycin ring I (Sati et al, 2017). The level of detail into modes of aminoglycoside binding that can now be obtained using cryo-EM thus should aid the use of chemical biology to advance AGA development.…”

Section: Discussionmentioning

confidence: 99%

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Structure of the bacterial ribosome at 2 Å resolution

Watson

Ward

Méheust

et al. 2020

eLife

208

225

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Using cryo-electron microscopy (cryo-EM), we determined the structure of the Escherichia coli 70S ribosome with a global resolution of 2.0 Å. The maps reveal unambiguous positioning of protein and RNA residues, their detailed chemical interactions, and chemical modifications. Notable features include the first examples of isopeptide and thioamide backbone substitutions in ribosomal proteins, the former likely conserved in all domains of life. The maps also reveal extensive solvation of the small (30S) ribosomal subunit, and interactions with A-site and P-site tRNAs, mRNA, and the antibiotic paromomycin. The maps and models of the bacterial ribosome presented here now allow a deeper phylogenetic analysis of ribosomal components including structural conservation to the level of solvation. The high quality of the maps should enable future structural analysis of the chemical basis for translation and aid the development of robust tools for cryo-EM structure modeling and refinement.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structure of the bacterial ribosome at 2 Å resolution

Watson

Ward

Méheust

et al. 2020

eLife

208

225

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“…Recent efforts have been made to make 4,5-linked aminoglycosides more selective for the bacterial ribosome. In one study, 4′-O modifications were installed on the 4,5linked aminoglycoside paromomycin and in another study, N6′-hydroxyethyl and 4′-O-ethyl modifications were installed on the neomycin core (167,168). In both cases, the modifications increased the ribosomal binding selectivity with little or no reduction in antibacterial potency (167).…”

Section: Design Strategies For Future Aminoglycosidesmentioning

confidence: 99%

“…In one study, 4′-O modifications were installed on the 4,5linked aminoglycoside paromomycin and in another study, N6′-hydroxyethyl and 4′-O-ethyl modifications were installed on the neomycin core (167,168). In both cases, the modifications increased the ribosomal binding selectivity with little or no reduction in antibacterial potency (167). Whether the improvement in ribosomal binding selectivity in favor of binding the bacterial versus eukaryotic ribosomes translates to a significant reduction in in vivo nephrotoxicity and ototoxicity remains to be tested.…”

Section: Design Strategies For Future Aminoglycosidesmentioning

confidence: 99%

Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation

Serio¹,

Keepers²,

Andrews³

et al. 2018

EcoSal Plus

118

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Aminoglycosides are cidal inhibitors of bacterial protein synthesis that have been utilized for the treatment of serious bacterial infections for almost 80 years. There have been approximately 15 members of this class approved worldwide for the treatment of a variety of infections, many serious and life threatening. While aminoglycoside use declined due to the introduction of other antibiotic classes such as cephalosporins, fluoroquinolones, and carbapenems, there has been a resurgence of interest in the class as multidrug-resistant pathogens have spread globally. Furthermore, aminoglycosides are recommended as part of combination therapy for empiric treatment of certain difficult-totreat infections. The development of semisynthetic aminoglycosides designed to overcome common aminoglycoside resistance mechanisms, and the shift to once-daily dosing, has spurred renewed interest in the class. Plazomicin is the first new aminoglycoside to be approved by the FDA in nearly 40 years, marking the successful start of a new campaign to rejuvenate the class. AMINOGLYCOSIDE HISTORY Aminoglycoside antimicrobials were first discovered in the 1940s and originally isolated from actinomycetes. Streptomycin, isolated from Streptomyces griseus, was the first aminoglycoside introduced into clinical practice for the treatment of tuberculosis (1, 2). Selman Waksman (the first to coin the term "antibiotic") won the Nobel Prize in 1952 for the discovery of streptomycin, along with Albert Schatz, who was eventually recognized as a codiscoverer. Since then, a number of aminoglycosides have been discovered as products from the Streptomyces group ("mycin" aminoglycosides, e.g., neomycin, kanamycin, tobramycin) or Micromonospora group ("micin" aminoglycosides, e.g., gentamicin, sisomicin) species, or developed through chemical modifications using existing aminoglycoside scaffolds (e.g., amikacin, netilmicin, arbekacin, plazomicin). Plazomicin is an aminoglycoside that was engineered to overcome aminoglycoside-modifying enzymes (AMEs), the most common aminoglycoside resistance mechanism in Enterobacteriaceae, and is the first aminoglycoside to be approved by the FDA (June 2018) since the approval of amikacin in 1981, marking the beginning of a class rejuvenation.

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“…9 To date, multiple AGs have been isolated and thousands of semi-synthetic derivatives have been synthesized in an attempt to improve their pharmacological properties and to reveal structure-activity relationship. [10][11][12][13][14][15][16] Only a handful of natural and semisynthetic AGs are currently in clinical use, however. These include neomycin, tobramycin, gentamicin, and the semisynthetic derivative of the natural AG kanamycin A known as amikacin 17 .…”

mentioning

confidence: 99%

The relationship between the structure and toxicity of aminoglycoside antibiotics

Jospe-Kaufman

Siomin

Fridman

2020

Bioorganic & Medicinal Chemistry Letters

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Aminoglycoside antibiotics, used to treat persistent gram-negative infections, tuberculosis, and life-threatening infections in neonates and patients with cystic fibrosis, can infer acute kidney injury and irreversible hearing loss. The full repertoire of cellular targets and processes leading to the toxicity of aminoglycosides is not fully resolved, making it challenging to devise rational directions to circumvent their adverse effects. As a result, there has been very limited effort to rationally address the issue of aminoglycoside-induced toxicity. Here we provide an overview of the reported effects of aminoglycosides on cells of the inner ear and on kidney tubular epithelial cells. We describe selected examples for structure-toxicity relationships established by evaluation of both natural and semisynthetic aminoglycosides. The various assays and models used to evaluate these antibiotics and recent progress in development of safer aminoglycoside antibiotics are discussed.

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N6′, N6′′′, and O4′ Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity

Cited by 15 publications

References 77 publications

Structure of the bacterial ribosome at 2 Å resolution

Structure of the bacterial ribosome at 2 Å resolution

Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation

The relationship between the structure and toxicity of aminoglycoside antibiotics

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