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Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance
- Source :
- Biochemical Journal. 454:191-200
- Publication Year :
- 2013
- Publisher :
- Portland Press Ltd., 2013.
-
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.
- Subjects :
- Acinetobacter baumannii
medicine.drug_class
Kanamycin kinase
Antibiotics
Molecular Conformation
Microbial Sensitivity Tests
Drug resistance
Biology
Biochemistry
Article
Microbiology
Structure-Activity Relationship
Antibiotic resistance
Bacterial Proteins
Kanamycin
Drug Resistance, Bacterial
Escherichia coli
medicine
Structure–activity relationship
Protein Kinase Inhibitors
Molecular Biology
Anthracenes
chemistry.chemical_classification
Binding Sites
Kanamycin Kinase
Aminoglycoside
Cell Biology
Recombinant Proteins
Anti-Bacterial Agents
Isoenzymes
Aminoglycosides
Pyrimidines
Enzyme
chemistry
Drug Design
Quinazolines
Pyrazoles
medicine.drug
Subjects
Details
- ISSN :
- 14708728 and 02646021
- Volume :
- 454
- Database :
- OpenAIRE
- Journal :
- Biochemical Journal
- Accession number :
- edsair.doi.dedup.....fba2b22d8cc70894dfe49695a0679893
- Full Text :
- https://doi.org/10.1042/bj20130317