ArticleThe Biochemical journal2013
Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance.
Article in The Biochemical journal, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 59 citations in OpenAlex.
- Preclinical Pharmacokinetics and Pharmacodynamics of Antibiotic Adjuvants.ACS infectious diseases · 2026Review
- Proteomic Insights into Antimicrobial Resistance Mechanisms in Human-Associated Bacterial Pathogens.Microbial ecology · 2026Review
- Targeting bacterial kinases as a strategy to counteract antibiotic resistance.Communications chemistry · 2025Article
- Fragment-based drug design of a bacterial kinase inhibitor capable of increasing the antibiotic sensitivity of clinical isolates.Communications chemistry · 2025Article
- Structural and evolutionary insights into understudied bacterial serine-threonine pseudokinase families.Biochemical Society transactions · 2025Review
- APH Inhibitors that Reverse Aminoglycoside Resistance in Enterococcus casseliflavus.ChemMedChem · 2025Article
- Multidrug Resistance, Biofilm-Forming Ability, and Molecular Characterization ofAntibiotics (Basel, Switzerland) · 2025Article
- Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistanteLife · 2025Article
- APH(3')-Ie, an aminoglycoside-modifying enzyme discovered in a rabbit-derivedFrontiers in cellular and infection microbiology · 2024Article
- Prevention and potential remedies for antibiotic resistance: current research and future prospects.Frontiers in microbiology · 2024Review
- Discovery and characterization of genes conferring natural resistance to the antituberculosis antibiotic capreomycin.Communications biology · 2023Article
- Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation.RSC medicinal chemistry · 2023Review
- Review
- Identification and characterization of a novel chromosomal aminoglycoside 3'-Frontiers in microbiology · 2023Article
- Intein-based Design Expands Diversity of Selenocysteine Reporters.Journal of molecular biology · 2022Article
- Review
- Article
- Structure of the full-length Serratia marcescens acetyltransferase AAC(3)-Ia in complex with coenzyme A.Protein science : a publication of the Protein Society · 2020Article
- Antibiotic resistance breakers: current approaches and future directions.FEMS microbiology reviews · 2019Review
- Drug combinations: a strategy to extend the life of antibiotics in the 21st century.Nature reviews. Microbiology · 2019Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Activity of the aminoglycoside phosphotransferase APH(3')-Ia leads to resistance to aminoglycoside antibiotics in pathogenic Gram-negative bacteria, and contributes to the clinical obsolescence of this class of antibiotics. One strategy to rescue compromised antibiotics such as aminoglycosides is targeting the enzymes that confer resistance with small molecules. We demonstrated previously that ePK (eukaryotic protein kinase) inhibitors could inhibit APH enzymes, owing to the structural similarity between these two enzyme families. However, limited structural information of enzyme-inhibitor complexes hindered interpretation of the results. In addition, cross-reactivity of compounds between APHs and ePKs represents an obstacle to their use as aminoglycoside adjuvants to rescue aminoglycoside antibiotic activity. In the present study, we structurally and functionally characterize inhibition of APH(3')-Ia by three diverse chemical scaffolds, anthrapyrazolone, 4-anilinoquinazoline and PP (pyrazolopyrimidine), and reveal distinctions in the binding mode of anthrapyrazolone and PP compounds to APH(3')-Ia compared with ePKs. Using this observation, we identify PP derivatives that select against ePKs, attenuate APH(3')-Ia activity and rescue aminoglycoside antibiotic activity against a resistant Escherichia coli strain. The structures described in the present paper and the inhibition studies provide an important opportunity for structure-based design of compounds to target aminoglycoside phosphotransferases for inhibition, potentially overcoming this form of antibiotic resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.