Rational design of berberine-based FtsZ inhibitors with broad-spectrum antibacterial activity
| Autor: | Hok-Kiu Lui, Ka-Yan Chow, Fung-Yi Chan, Ning Sun, Siu-Cheong Yan, Ruben Abagyan, Kwok Yin Wong, Yu-Jing Lu, Kin-Fai Chan, Tak Hang Chan, Yong Wang, Yun Chung Leung, Marco A. C. Neves |
|---|---|
| Přispěvatelé: | Scheffers, Dirk-Jan |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Berberine Protein Conformation lcsh:Medicine Biochemistry chemistry.chemical_compound Models Drug Discovery Macromolecular Structure Analysis Medicine and Health Sciences lcsh:Science Microscopy Multidisciplinary biology Molecular Structure Alkaloid Gram Positive Bacteria Antimicrobial Bacterial Pathogens Anti-Bacterial Agents Chemistry Infectious Diseases 5.1 Pharmaceuticals Medical Microbiology Physical Sciences Development of treatments and therapeutic interventions Antibacterial activity Infection Research Article Drug Research and Development General Science & Technology Microbial Sensitivity Tests macromolecular substances Gram-Positive Bacteria Electron Microbiology Bacterial Proteins Microscopy Electron Transmission Microbial Control Complementary and Integrative Health Chemical Biology Escherichia coli Transmission FtsZ Benzylisoquinoline Gram Negative Bacteria Microbial Pathogens Molecular Biology Pharmacology Organic Chemistry Organic Synthesis lcsh:R Rational design Molecular Biology and Life Sciences Computational Biology Bacteriology biology.organism_classification Cytoskeletal Proteins Emerging Infectious Diseases chemistry biology.protein lcsh:Q Antimicrobial Resistance Bacteria |
| Zdroj: | PLoS ONE, Vol 9, Iss 5, p e97514 (2014) PLoS ONE PloS one, vol 9, iss 5 |
| ISSN: | 1932-6203 |
| Popis: | Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ) protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of in silico structure-based design and in vitro biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ. |
| Databáze: | OpenAIRE |
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