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Title: Protoberberine derivatives as potent inhibitors of the bacterial cell division protein FtsZ
Authors: Sun, Ning
Degree: Ph.D.
Issue Date: 2013
Abstract: Antibiotic-resistant bacterial infection has become epidemic all over the world. To overcome the drug resistance problem, existing antibiotics have been modified extensively to preserve activity against their targets. Due to the low efficiency and great difficulties of chemical modification, antibacterial agents targeting at new sites become critical to solve this problem. FtsZ (filamenting temperature sensitive strain Z), a bacterial cell division protein, has become attractive as a new target for antibacterial agents discovery because it is the most important and conserved protein in bacterial cytokinesis. Nowadays, several compounds that inhibit the biological activity of the FtsZ protein and block the bacterial cell division have been reported, and most of them bind either to the GTP binding pocket or the H7 helix. However, none of these compounds have entered clinical trials yet. Natural products are important sources for drug discovery and development and many of them show tolerable toxicity on humans. Berberine and palmatine, which are alkaloids in the protoberberine group from herbs, are known to exhibit various pharmacological effects, such as antibacterial, anti-arrhythmia and anti-cancer. A recent report revealed that berberine binds to FtsZ in the hydrophobic region of the GTP binding pocket, destabilizes FtsZ protofilaments, inhibits the FtsZ GTPase activity and shows antibacterial activities though the effects are relatively weak. In this study, berberine and palmatine were chosen as lead compounds for further modification. Two series of compounds, 9-phenoxyalkyl berberines and 9-phenoxyalkyl palmatines, were synthesized, and their antibacterial activity and interactions with FtsZ protein were investigated. The results showed that these protoberberine derivatives exhibited greatly improved antibacterial activities against a broad spectrum of bacteria with enhanced inhibitory effect on the GTP hydrolysis and polymerization of FtsZ. These derivatives have IC50 values of GTPase activity in the range of 30- 80 μM, which are 4- 9 folds stronger than their parent compounds. In addition, all of them possess a potent antimicrobial activity with MIC values in the range of 2- 64 μg/mL against Gram-positive bacterial strains and show a moderate inhibition against Gram-negative strains. Among them, compound B2 was identified as the most potent derivatives against bacterial strains. B2 not only inhibits the growth of E. coli with an MIC value of 32 μg/mL, but also exhibits an impressive activity against S. aureus, including methicillin and ampicillin resistant S. aureus, with an MIC value of 2 μg/mL.
Molecular docking of these derivatives to the FtsZ protein suggested that the berberine or palmatine core bound to the GTP binding site while the phenoxy moiety interacted with the residues at the C-terminal domain of another FtsZ monomer. This bivalent binding at different locations on two adjacent FtsZ monomers might explain the improved activities of these synthetic compounds compared to their parent compounds which only bind to the GTP binding pocket. To assess the potential of B2 and P2 in treating bacterial infections, the synergistic effects in combination with some conventional antibiotics and the cytotoxicity effects on some mammalian cell lines were investigated. B2 and P2 exhibited a synergistic or partial synergistic effect with conventional antibiotics against drug-resistant bacterial strains. The results of cytotoxicity test showed that these two compounds are toxic to mammalian cells, but the toxicity of B2 can be reduced to an acceptable range when it is used together with ampicillin to treat drug-resistant S. aureus.
Subjects: Drug development.
Antibacterial agents.
Hong Kong Polytechnic University -- Dissertations
Berberine -- Therapeutic use.
Pages: xvii, 260 leaves : ill. (some col.) ; 30 cm.
Appears in Collections:Thesis

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