Aminoglycoside Antibiotics

Wright, Gerard D.; Berghuis, A.M.; Mobashery, Shahriar

doi:10.1007/978-1-4615-4897-3_4

Cited by 129 publications

(53 citation statements)

References 210 publications

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“…6 Aminoglycosides are one class of antibiotics that have been used clinically to treat bacterial infections for over five decades. 7 They interact with many different RNAs, including the hammerhead ribozyme, 8 HIV-1 mRNA, 9-11 tRNA Phe,12 the T box antiterminator RNA, 13 and the 16S bacterial ribosome. 14-16 The binding of aminoglycosides to bacterial ribosomes is of particular interest, since this is believed to be the clinically relevant target site.…”

Section: Introductionmentioning

confidence: 99%

Monitoring aminoglycoside-induced conformational changes in 16S rRNA through acrylamide quenching

Chao

Chow

2007

Bioorganic & Medicinal Chemistry

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Fluorescence of 2-aminopurine (2AP) substituted A site and acrylamide quenching were used to study the interactions of paromomycin and neamine with the decoding region of 16S rRNA. The results reveal that paromomycin binding to the A-site RNA leads to increased exposure of residue A1492. In contrast, neamine has little effect on the solvent accessibility of A1492. Electrospray ionization mass spectrometry was used to compare the affinity of paromomycin with the A-site and 2-AP-substituted A-site RNAs.

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Section: Introductionmentioning

confidence: 99%

Monitoring aminoglycoside-induced conformational changes in 16S rRNA through acrylamide quenching

Chao

Chow

2007

Bioorganic & Medicinal Chemistry

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“…The enzymes encoded by these genes modify the structures of antibiotics, such that the modified drugs bind poorly to their targets. Among these antibiotic resistance enzymes, those for aminoglycoside antibiotics are widespread in pathogens (1)(2)(3)(4)(5). Of these enzymes, the aminoglycoside 3Ј-phosphotransferases (APH(3Ј)s) 2 are the most common, and they are responsible for the demise of kanamycin, among other aminoglycosides, as a treatment option.…”

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Hydrolysis of ATP by Aminoglycoside 3′-Phosphotransferases

Kim

Young

Yan

et al. 2006

Journal of Biological Chemistry

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Aminoglycoside 3-phosphotransferases (APH(3)s) are common bacterial resistance enzymes to aminoglycoside antibiotics. These enzymes transfer the ␥-phosphoryl group of ATP to the 3-hydroxyl of the antibiotics, whereby the biological activity of the drugs is lost. Pre-steady-state and steady-state kinetics with two of these enzymes from Gram-negative bacteria, APH(3)-Ia and APH(3)-IIa, were performed. It is demonstrated that these enzymes in both ternary and binary complexes facilitate an ATP hydrolase activity (ATPase), which is competitive with the transfer of phosphate to the antibiotics. Because these enzymes are expressed constitutively in resistant bacteria, the turnover of ATP is continuous during the lifetime of the organism both in the absence and the presence of aminoglycosides. Concentrations of the enzyme in vivo were determined, and it was estimated that in a single generation of bacterial growth there exists the potential that this activity would consume as much as severalfold of the total existing ATP. Studies with bacteria harboring the aph(3)-Ia gene revealed that bacteria are able to absorb the cost of this ATP turnover, as ATP is recycled. However, the cost burden of this adventitious activity manifests a selection pressure against maintenance of the plasmids that harbor the aph(3)-Ia gene, such that ϳ50% of the plasmid is lost in 1500 bacterial generations in the absence of antibiotics. The implication is that, in the absence of selection, bacteria harboring an enzyme that catalyzes the consumption of key metabolites could experience the loss of the plasmid that encodes for the given enzyme.

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“…1 below) are widely used in the treatment of bacterial infections caused by both Grampositive and Gram-negative pathogens yet the specific details of the molecular mechanisms of resistance to this class of antibiotics remain largely unknown. Aminoglycosides act first by disrupting protein expression and interfering with translation at the level of appropriate aminoacyl-tRNA recognition at the ribosomal A site; this is followed by a series of secondary effects, including membrane damage, which combine to arrest growth and kill the cell (1). The ribosomal receptor for most aminoglycoside antibiotics, including gentamicin C, kanamycin, and neomycin, is the 16 S rRNA of the 30 S subunit.…”

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confidence: 99%

“…The aminoglycoside kinases (abbreviated APH) 1 include a number of enzymes with differing aminoglycoside substrate specificities and regiospecificities of phosphoryl transfer. Despite this broad tolerance for aminoglycoside substrates, all APHs share a common active site motif that resembles the active site residues found in the Ser/Thr/Tyr protein kinase superfamily (9).…”

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confidence: 99%

Molecular Mechanism of Aminoglycoside Antibiotic Kinase APH(3′)-IIIa

Boehr¹,

Thompson²,

Wright

2001

Journal of Biological Chemistry

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The aminoglycoside antibiotic kinases (APHs) constitute a clinically important group of antibiotic resistance enzymes. APHs share structural and functional homology with Ser/Thr and Tyr kinases, yet only five amino acids are invariant between the two groups of enzymes and these residues are all located within the nucleotide binding regions of the proteins. We have performed sitedirected mutagenesis on all five conserved residues in the aminoglycoside kinase APH (3)

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Aminoglycoside Antibiotics

Cited by 129 publications

References 210 publications

Monitoring aminoglycoside-induced conformational changes in 16S rRNA through acrylamide quenching

Monitoring aminoglycoside-induced conformational changes in 16S rRNA through acrylamide quenching

Hydrolysis of ATP by Aminoglycoside 3′-Phosphotransferases

Molecular Mechanism of Aminoglycoside Antibiotic Kinase APH(3′)-IIIa

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