ArticlePloS one2011
Crystal structures of two aminoglycoside kinases bound with a eukaryotic protein kinase inhibitor.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Fragment-based drug design of a bacterial kinase inhibitor capable of increasing the antibiotic sensitivity of clinical isolates.Communications chemistry · 2025Article
- APH Inhibitors that Reverse Aminoglycoside Resistance in Enterococcus casseliflavus.ChemMedChem · 2025Article
- Whole Genome Sequencing ofMicroorganisms · 2024Article
- Prevention and potential remedies for antibiotic resistance: current research and future prospects.Frontiers in microbiology · 2024Review
- Alpha-Naphthoflavone as a Novel Scaffold for the Design of Potential Inhibitors of the APH(3')-IIIa Nucleotide-Binding Site ofMicroorganisms · 2023Article
- Review
- Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks?Infection · 2021Review
- Structural basis for the substrate recognition of aminoglycoside 7''-phosphotransferase-Ia from Streptomyces hygroscopicus.Acta crystallographica. Section F, Structural biology communications · 2019Article
- Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug-Resistant Pseudomonas aeruginosa Clinical Isolates.Microbial drug resistance (Larchmont, N.Y.) · 2018Article
- Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities.Chemical Society reviews · 2018Review
- Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens.Frontiers in microbiology · 2018Review
- Synthesis and Biological Activity of Mono- and Di-N-acylated Aminoglycosides.ACS medicinal chemistry letters · 2015Article
- New trends in aminoglycosides use.MedChemComm · 2014Article
- Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance.The Biochemical journal · 2013Article
- Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections.Future medicinal chemistry · 2013Review
- Preliminary crystallographic analysis of the kinase domain of SAD-1, a protein essential for presynaptic differentiation in Caenorhabditis elegans.Acta crystallographica. Section F, Structural biology and crystallization communications · 2013Article
- Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases.PLoS pathogens · 2013Article
- Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance.Frontiers in cellular and infection microbiology · 2013Review
- Structural basis for dual nucleotide selectivity of aminoglycoside 2''-phosphotransferase IVa provides insight on determinants of nucleotide specificity of aminoglycoside kinases.The Journal of biological chemistry · 2012Article
- Understanding and overcoming aminoglycoside resistance caused by N-6'-acetyltransferase.MedChemComm · 2012Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Antibiotic resistance is recognized as a growing healthcare problem. To address this issue, one strategy is to thwart the causal mechanism using an adjuvant in partner with the antibiotic. Aminoglycosides are a class of clinically important antibiotics used for the treatment of serious infections. Their usefulness has been compromised predominantly due to drug inactivation by aminoglycoside-modifying enzymes, such as aminoglycoside phosphotransferases or kinases. These kinases are structurally homologous to eukaryotic Ser/Thr and Tyr protein kinases and it has been shown that some can be inhibited by select protein kinase inhibitors. The aminoglycoside kinase, APH(3')-IIIa, can be inhibited by CKI-7, an ATP-competitive inhibitor for the casein kinase 1. We have determined that CKI-7 is also a moderate inhibitor for the atypical APH(9)-Ia. Here we present the crystal structures of CKI-7-bound APH(3')-IIIa and APH(9)-Ia, the first structures of a eukaryotic protein kinase inhibitor in complex with bacterial kinases. CKI-7 binds to the nucleotide-binding pocket of the enzymes and its binding alters the conformation of the nucleotide-binding loop, the segment homologous to the glycine-rich loop in eukaryotic protein kinases. Comparison of these structures with the CKI-7-bound casein kinase 1 reveals features in the binding pockets that are distinct in the bacterial kinases and could be exploited for the design of a bacterial kinase specific inhibitor. Our results provide evidence that an inhibitor for a subset of APHs can be developed in order to curtail resistance to aminoglycosides.
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