6-Hydroxy to 6‴-amino tethered ring-to-ring macrocyclic aminoglycosides as probes for APH(3′)-IIIa kinase

Hanessian, Stephen; Szychowski, Janek; Pineda, Natalhie B. Campos-Reales; Fürtös, Alexandra; Keillor, Jeffrey W.

doi:10.1016/j.bmcl.2007.03.014

Cited by 13 publications

(11 citation statements)

References 43 publications

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“…Nonetheless, incidents of resistance to these semisynthetic N1-substituted aminoglycosides are slowly rising, including those to arbekacin, the most recent addition to the aminoglycoside antibiotic arsenal (3). Previously, the crystal structures of various aminoglycoside-bound A site and kanamycin A-or neomycin B-bound ternary complexes of APH(3Ј)-IIIa (18) have contributed to the design of several promising paromomycin derivatives (19)(20)(21). The additional information provided by the butirosin A crystal structure and the amikacin-bound model of APH(3Ј)-IIIa reported here could be implemented to further improve the prospect of new aminoglycoside derivatives.…”

Section: Resultsmentioning

confidence: 90%

Structural Basis of APH(3′)-IIIa-Mediated Resistance to N1-Substituted Aminoglycoside Antibiotics

Fong

Berghuis

2009

Antimicrob Agents Chemother

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Butirosin is unique among the naturally occurring aminoglycosides, having a substituted amino group at position 1 (N1) of the 2-deoxystreptamine ring with an (S)-4-amino-2-hydroxybutyrate (AHB) group. While bacterial resistance to aminoglycosides can be ascribed chiefly to drug inactivation by plasmid-encoded aminoglycoside-modifying enzymes, the presence of an AHB group protects the aminoglycoside from binding to many resistance enzymes, and hence, the antibiotic retains its bactericidal properties. Consequently, several semisynthetic N1-substituted aminoglycosides, such as amikacin, isepamicin, and netilmicin, were developed.

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Section: Resultsmentioning

confidence: 90%

Structural Basis of APH(3′)-IIIa-Mediated Resistance to N1-Substituted Aminoglycoside Antibiotics

Fong

Berghuis

2009

Antimicrob Agents Chemother

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“…44–48 In contrast, a more facile introduction of functionalities in structurally complex molecules generally depends on non-covalent protecting group strategies 49, 50 and enzymatic approaches. 51 …”

Section: Aminoglycosides As Antibacterial Agentsmentioning

confidence: 99%

A review of patents (2011–2015) towards combating resistance to and toxicity of aminoglycosides

Chandrika

Garneau‐Tsodikova

2016

Med. Chem. Commun.

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Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-negative and Gram-positive bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) associated with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concentration by efflux pumps have resulted in resistance towards AGs. However, the last decade has seen a renewed interest among the scientific community for AGs as exemplified by the recent influx of scientific articles and patents on their therapeutic use. In this review, we use a non-conventional approach to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011–2015 and highlighting some related publications on the most recent work done on AGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity. We also present work towards developing amphiphilic AGs for use as fungicides as well as that towards repurposing existing AGs for potential newer applications.

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“…However, in contrast to many ePKs that undergo a substantial conformation change from the open to closed state upon ligand binding, the structural differences between apo and ligand-bound APH(3Ј)-IIIa (and inferred for APH(3Ј)-IIa and APH(2Љ)-IIa) are localized (12). These crystal structures have provided crucial infor-mation for the development of new antibiotics and inhibitors (17)(18)(19)(20)(21).…”

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Structure of the Antibiotic Resistance Factor Spectinomycin Phosphotransferase from Legionella pneumophila

Fong

Lemke

Hwang

et al. 2010

Journal of Biological Chemistry

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Aminoglycoside phosphotransferases (APHs) constitute a diverse group of enzymes that are often the underlying cause of aminoglycoside resistance in the clinical setting. Several APHs have been extensively characterized, including the elucidation of the three-dimensional structure of two APH(3) isozymes and an APH(2؆) enzyme. Although many APHs are plasmid-encoded and are capable of inactivating numerous 2-deoxystreptmaine aminoglycosides with multiple regiospecificity, APH(9)-Ia, isolated from Legionella pneumophila, is an unusual enzyme among the APH family for its chromosomal origin and its specificity for a single non-2-deoxystreptamine aminoglycoside substrate, spectinomycin. We describe here the crystal structures of APH(9)-Ia in its apo form, its binary complex with the nucleotide, AMP, and its ternary complex bound with ADP and spectinomycin. The structures reveal that APH(9)-Ia adopts the bilobal protein kinase-fold, analogous to the APH(3) and APH(2؆) enzymes. However, APH(9)-Ia differs significantly from the other two types of APH enzymes in its substrate binding area and that it undergoes a conformation change upon ligand binding. Moreover, kinetic assay experiments indicate that APH(9)-Ia has stringent substrate specificity as it is unable to phosphorylate substrates of choline kinase or methylthioribose kinase despite high structural resemblance. The crystal structures of APH(9)-Ia demonstrate and expand our understanding of the diversity of the APH family, which in turn will facilitate the development of new antibiotics and inhibitors.Aminoglycosides are a class of commonly used broadspectrum antibiotics that target the bacterial ribosome. They are characterized by their signature chemical structure, an aminocyclitol nucleus. These antibiotics can be further categorized into two groups: the first group includes those that contain a 2-deoxystreptamine core, such as kanamycin, and the second, smaller group includes those that contain a non-2-deoxystreptamine core (Fig. 1A). Spectinomycin has a streptamine core and it is used in the treatment of acute gonococcal infections (1). Unfortunately, the efficacy of aminoglycosides has been compromised due to the continuous rise of drug resistance in pathogens. Resistance to aminoglycosides can be attributed to several mechanisms, of which enzymatic inactivation of the aminoglycoside is the most prevalent in the clinical setting. Aminoglycosides can be inactivated by the addition of an acetyl, a nucleotidyl, or a phosphate group by acetyltransferases, nucleotidyltransferases, or phosphotransferases (kinases; APHs), 5 respectively (2). Nomenclature of aminoglycoside-modifying enzymes follows the convention proposed by Shaw et al. (2): the type of modifying enzyme is identified by acetyltransferase, nucleotidyltransferase, or APH; this is followed by, in parentheses, the enzyme regiospecificity; then the substrate profile is designated by a roman numeral, and the unique amino acid sequence is denoted by a small letter.APHs generally yield high levels of resista...

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6-Hydroxy to 6‴-amino tethered ring-to-ring macrocyclic aminoglycosides as probes for APH(3′)-IIIa kinase

Cited by 13 publications

References 43 publications

Structural Basis of APH(3′)-IIIa-Mediated Resistance to N1-Substituted Aminoglycoside Antibiotics

Structural Basis of APH(3′)-IIIa-Mediated Resistance to N1-Substituted Aminoglycoside Antibiotics

A review of patents (2011–2015) towards combating resistance to and toxicity of aminoglycosides

Structure of the Antibiotic Resistance Factor Spectinomycin Phosphotransferase from Legionella pneumophila

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