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Prospects of Pre-clinical [6.6.0] Bicyclic Nitrogen Heterocycles in the Treatment of Tuberculosis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Neha P. Agre, Mariam S. Degani, Sanjib Bhakta
The protein FtsZ, homolog of bacterial tubulin, is a new target being explored for mycobacterial and other bacterial infections. FtsZ has a GTPase site characteristic of eukaryotic tubulins but exhibits low sequence similarity and differs in function. Its principal role is contractile Z ring formation which is vital for septation of bacteria, and like its mammalian couterpart it is not involved in chromosomal separation during mitosis. Reynolds et al. explored the potential of 2-carbamoyl analogues of pteridine and 3-deazapteridine as prospective FtsZ and TB inhibitors. The MIC of the 2-carbamoyl pteridine analogue 78 (Table 7) against Mtb H37Ra was found to be 2 μg/mL and the 3-deazapteridine analogue 79 (Table 7) had MIC of 0.25 μg/mL, determined using MABA assay. The pteridine analogue was as potent as the 3-deazapteridine in inhibiting FtsZ polymerisation but was a less potent inhibitor of GTP hydrolysis. Though GTP hydrolysis and FtsZ polymerisation were interconnected, the reason for this is not known. The pteridine scaffold was an acceptable substitution in terms of the FtsZ polymerisation but as far as the in vitro anti-tuberculosis activity is concerned, it is 8-fold less potent than the 3-deazapteridine analogue (Reynolds et al. 2004).
Mycobacterium
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Verlaine J. Timms, Brett Anthony Neilan
How mycobacteria manage to survive in the dormant state and then “switch” to the replicative and infectious state has been the subject of decades of research. The complex cell wall of mycobacteria provides a challenge to cell division and is a focus for many studies into mycobacterial latency regulation. Mycobacteria display a flexible mode of apical growth, where peptidoglycan precursors are added at cell poles.12 When the cell has reached its limit of growth, building of the cell wall is shifted to the potential division site marked by the FtsZ ring leading to the formation of the characteristic V-shape of dividing mycobacteria.12
Mode of Action of Selected Botanicals That Lower Blood Glucose
Published in Robert Fried, Richard M. Carlton, Type 2 Diabetes, 2018
Robert Fried, Richard M. Carlton
Berberine has significant antimicrobial activity against several microbes through inhibiting the assembly function of “Filamenting temperature-sensitive mutant Z” (FtsZ) and halting bacterial cell division. FtsZ is a cell-division protein. Because berberine acts topically in the gastrointestinal tract and is poorly absorbed, berberine might modulate gut microbiota without systemic anti-infective activity. The authors hypothesized that gut microbiota modulation may be one mechanism of the antidiabetic effect of berberine (Han, Lin, and Huang. 2011).
Curcumin: footprints on cardiac tissue engineering
Published in Expert Opinion on Biological Therapy, 2019
Saeid Kargozar, Francesco Baino, Seyed Javad Hoseini, Javad Verdi, Shiva Asadpour, Masoud Mozafari
Similar to the above-mentioned biological properties, anti-bacterial effects of biomaterials also are of great importance for cardiac tissue engineering. For instance, Mahmoudi et al. in 2016 developed infection-resistant MRI-visible patches for cardiac tissue engineering by incorporating superparamagnetic iron oxide nanoparticles (SPIONs) into this patch [32]. Studies show that curcumin possesses anti-bacterial features through the interaction with the essential cell division initiating protein FtsZ [33,34]. FtsZ is an essential protein in most prokaryotes, responding for bacterial cell division. It has been identified that the methoxy and hydroxyl groups of curcumin are indeed involved in its antimicrobial activity [35,36]. The minimum inhibitory concentration (MIC) of curcumin has been previously evaluated for both Gram-positive and Gram-negative bacterial strains by Gunes et al. [37]. They reported that the curcumin showed anti-bacterial effects against Pseudomonas aeruginosa (175 mg/mL), Bacillus subtilis (129 mg/mL), methicillin-sensitive Staphylococcus aureus (219 mg/mL), methicillin-resistant S. aureus (217 mg/mL), Escherichia coli (163 mg/mL), Enterococcus faecalis (293 mg/mL), and Klebsiella pneumoniae (216 mg/mL).
Discovery of promising FtsZ inhibitors by E-pharmacophore, 3D-QSAR, molecular docking study, and molecular dynamics simulation
Published in Journal of Receptors and Signal Transduction, 2019
Yaping Qiu, Lu Zhou, Yanqiu Hu, Yinfeng Bao
The distance and the angle between different sites of HHRR.4 are shown in Figure 1(A,B). The two hydrophobic groups (H3 and H5) were represented by green spheres, and the two aromatic rings (R7 and R8) were shown in brown circles. They reflected the characteristic structure of FtsZ inhibitors that played an important role in the activity. Analysis of the structural characteristics of the 63 inhibitors indicated that they have functional groups capable of forming hydrophobic and aromatic rings, indicating the rationality of the constructed pharmacophore. It also showed that the molecules that could inhibit FtsZ must match the distance and angle of pharmacophore sites. The alignment of all the molecules on HHRR.4 with respect to active and inactive data-set was shown in Figure 1(C,D).
Structural insights of Staphylococcus aureus FtsZ inhibitors through molecular docking, 3D-QSAR and molecular dynamics simulations
Published in Journal of Receptors and Signal Transduction, 2018
Srilata Ballu, Ramesh Itteboina, Sree Kanth Sivan, Vijjulatha Manga
The prevailing numbers of bacterial infections that are resistant to known antibiotic therapies have an urgency to identify new antibiotics with novel mechanism of action. Septum formation during bacterial cell division involves protein-protein interaction network. Filamentous temperature-sensitive protein Z (FtsZ) is homologous to eukaryotic tubulin that polymerizes into ring like structure at the mid cell and plays a central role in the protein network [1]. FtsZ is also the first protein to move to the division site and recruits other proteins that produce a new cell wall between the dividing cells. The proteins that are localized to the FtsZ polymer during the cell cycle include FtsA, FtsI, ZipA and others. There is considerable evidence to illustrate that the interaction between FtsA and FtsZ is essential for bacterial cell division [2–4]. FtsZ is an attractive new pharmacological target for the development of antibacterial agent. There are few molecules synthesized [5–7] virtual screened [8] and a 3 D-quantitative structure-activity relationship models (QSAR) study [9] that target the FtsZ protein, reveal that benzamide type of inhibitors as antibacterial drugs restrict the conformational changes in FtsZ.