ArticleMolecular pharmaceutics2018
In Silico Screen and Structural Analysis Identifies Bacterial Kinase Inhibitors which Act with β-Lactams To Inhibit Mycobacterial Growth.
Article in Molecular pharmaceutics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 29 citations in OpenAlex.
- Structural insights into multitargetingMicrobiology spectrum · 2026Article
- Structural Modification of Indole Derivatives as PknB Inhibitors for Enhanced Enzymatic Inhibition and Antimycobacterial Activity.ACS omega · 2026Article
- Integrative computational approaches, molecular docking, and dynamic simulations reveal the antimycobacterial activity of fisetin as a potential inhibitor of Mycobacterium tuberculosis.Journal of computer-aided molecular design · 2026Article
- Identification and characterization of inhibitors of the tuberculosis phosphatase PstP.The Journal of biological chemistry · 2026Article
- Structure, Mutation, Functional Domain Roles and Medical Implications of Glycerol Kinase.The protein journal · 2026Review
- Multifaceted Small Molecules as Enzyme Modulators: Cases of Drug Discovery/Repurposing Illustrating Nature's Pragmatism.BioMed research international · 2026Review
- Identification of Anti-Tuberculosis Drugs Targeting DNA Gyrase A and Serine/Threonine Protein Kinase PknB: A Machine Learning-Assisted Drug-Repurposing Approach.Tropical medicine and infectious disease · 2024Article
- Utilization of Existing Human Kinase Inhibitors as Scaffolds in the Development of New Antimicrobials.Antibiotics (Basel, Switzerland) · 2023Review
- Identification of potential RapJ hits as sporulation pathway inducer candidates in Bacillus coagulans via structure-based virtual screening and molecular dynamics simulation studies.Journal of molecular modeling · 2023Article
- Conformational changes in the activation loop of a bacterial PASTA kinase.Protein science : a publication of the Protein Society · 2023Article
- Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives.Antibiotics (Basel, Switzerland) · 2022Article
- Article
- Evaluation of small molecule kinase inhibitors as novel antimicrobial and antibiofilm agents.Chemical biology & drug design · 2021Review
- An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis.Molecules (Basel, Switzerland) · 2021Review
- In Silico Identification of Possible Inhibitors for Protein Kinase B (PknB) ofMolecules (Basel, Switzerland) · 2021Article
- Review
- β-Lactams against the Fortress of the Gram-PositiveChemical reviews · 2021Review
- Engineering Selectivity for Reduced Toxicity of Bacterial Kinase Inhibitors Using Structure-Guided Medicinal Chemistry.ACS medicinal chemistry letters · 2021Article
- Structure of theCurrent research in structural biology · 2021Article
- Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility.PLoS pathogens · 2020Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
New tools and concepts are needed to combat antimicrobial resistance. Actinomycetes and firmicutes share several eukaryotic-like Ser/Thr kinases (eSTK) that offer antibiotic development opportunities, including PknB, an essential mycobacterial eSTK. Despite successful development of potent biochemical PknB inhibitors by many groups, clinically useful microbiologic activity has been elusive. Additionally, PknB kinetics are not fully described, nor are structures with specific inhibitors available to inform inhibitor design. We used computational modeling with available structural information to identify human kinase inhibitors predicted to bind PknB, and we selected hits based on drug-like characteristics intended to increase the likelihood of cell entry. The computational model suggested a family of inhibitors, the imidazopyridine aminofurazans (IPAs), bind PknB with high affinity. We performed an in-depth characterization of PknB and found that these inhibitors biochemically inhibit PknB, with potency roughly following the predicted models. A novel X-ray structure confirmed that the inhibitors bound as predicted and made favorable protein contacts with the target. These inhibitors also have antimicrobial activity toward mycobacteria and nocardia. We demonstrated that the inhibitors are uniquely potentiated by β-lactams but not antibiotics traditionally used to treat mycobacteria, consistent with PknB's role in sensing cell wall stress. This is the first demonstration in the phylum actinobacteria that some β-lactam antibiotics could be more effective if paired with a PknB inhibitor. Collectively, our data show that in silico modeling can be used as a tool to discover promising drug leads, and the inhibitors we discovered can act with clinically relevant antibiotics to restore their efficacy against bacteria with limited treatment options.
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Registered trials
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