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Yogavel Manickam Nipun Malhotra Siddhartha Mishra Palak Babbar Abhishek Dusane Benoît Laleu Valeria Bellini Mohamed-Ali Hakimi Alexandre Bougdour Amit Sharma 《PLoS pathogens》2022,18(3)
Toxoplasmosis is caused by Toxoplasma gondii and in immunocompromised patients it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) is a validated druggable target in Toxoplasma gondii but the traditional ‘single target–single drug’ approach has its caveats. Here, we describe two potent inhibitors namely halofuginone (HFG) and a novel ATP mimetic (L95) that bind to Toxoplasma gondii PRS simultaneously at different neighbouring sites to cover all three of the enzyme substrate subsites. HFG and L95 act as one triple-site inhibitor in tandem and form an unusual ternary complex wherein HFG occupies the 3’-end of tRNA and the L-proline (L-pro) binding sites while L95 occupies the ATP pocket. These inhibitors exhibit nanomolar IC50 and EC50 values independently, and when given together reveal an additive mode of action in parasite inhibition assays. This work validates a novel approach and lays a structural framework for further drug development based on simultaneous targeting of multiple pockets to inhibit druggable proteins. 相似文献
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Dusane DH Pawar VS Nancharaiah YV Venugopalan VP Kumar AR Zinjarde SS 《Biofouling》2011,27(6):645-654
A tropical marine bacterium isolated from the hard coral, Symphyllia sp. was identified as Serratia marcescens on the basis of morphological, biochemical and 16S rDNA analysis. The bacterium showed antimicrobial activity towards the pathogens Candida albicans and Pseudomonas aeruginosa and the marine biofouling bacterium Bacillus pumilus. S. marcescens displayed biosurfactant activity as evidenced by drop collapse, blood hemolysis and surface tension reduction (52.0-27 mN m(-1)). The active compound was purified by solvent extraction and silicic acid chromatography. Characterization was by thin layer chromatography, gas chromatography mass spectroscopy (GC-MS), Fourier transform infrared (FTIR) spectroscopy and (1)H as well as (13)C nuclear magnetic resonance (NMR) analysis. The surfactant was found to be a glycolipid composed of glucose and palmitic acid. The glycolipid prevented adhesion of C. albicans BH, P. aeruginosa PAO1 and B. pumilus TiO1. The glycolipid also disrupted preformed biofilms of these cultures in microtitre plates. Confocal laser scanning microscopy and electron microscopy confirmed the effective removal of biofilms from glass surfaces. The glycolipid derived from S. marcescens could thus serve as a potential anti-biofilm agent. 相似文献
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We have evaluated codon usage bias in Drosophila histone genes and have
obtained the nucleotide sequence of a 5,161-bp D. hydei histone gene repeat
unit. This repeat contains genes for all five histone proteins (H1, H2a,
H2b, H3, and H4) and differs from the previously reported one by a second
EcoRI site. These D. hydei repeats have been aligned to each other and to
the 5.0-kb (i.e., long) and 4.8-kb (i.e., short) histone repeat types from
D. melanogaster. In each species, base composition at synonymous sites is
similar to the average genomic composition and approaches that in the small
intergenic spacers of the histone gene repeats. Accumulation of synonymous
changes at synonymous sites after the species diverged is quite high. Both
of these features are consistent with the relatively low codon usage bias
observed in these genes when compared with other Drosophila genes. Thus,
the generalization that abundantly expressed genes in Drosophila have high
codon bias and low rates of silent substitution does not hold for the
histone genes.
相似文献
4.
D.H. Dusane J.K. Rajput A.R. Kumar Y.V. Nancharaiah V.P. Venugopalan S.S. Zinjarde 《Letters in applied microbiology》2008,47(5):374-379
Aim: The ability of enzymatically synthesized lauroyl glucose to disrupt fungal (Candida albicans, Candida lipolytica) and bacterial (Pseudomonas aeruginosa PAO1, Pseudomonas aureofaciens) biofilms was investigated. Methods and Results: Preformed biofilms of C. albicans and C. lipolytica in polystyrene microtitre plates were disrupted upto 45% and 65%, respectively, while P. aeruginosa and P. aureofaciens biofilms were disrupted by 51% and 57%. Precoating of the microtitre wells with lauroyl glucose affected cell attachment and biofilm growth of all the cultures to a lesser extent. With C. albicans and C. lipolytica, there was 11% and 32% decrease in the development of biofilms, respectively. With P. aeruginosa and P. aureofaciens, the reduction was 21% and 12% after 48 h. Lauroyl glucose effectively inhibited the formation of biofilms on glass slide surfaces when added along with the inoculum. Analysis by confocal laser scanning microscopy showed that the growth of the biofilms was lesser as compared with the control experiments. Lauroyl glucose displayed minimum inhibitory concentration values >500 μg ml?1 for the test cultures and was comparable to that obtained with acetyl salicylate. Conclusion: Lauroyl glucose reduces biofilm growth of all the four test cultures on polystyrene and glass surfaces. Significance and Impact of the Study: This report is a novel application of the enzymatically synthesized, environmental‐friendly nonionic surfactant. 相似文献
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Dusane DH Dam S Nancharaiah YV Kumar AR Venugopalan VP Zinjarde SS 《Aquatic biosystems》2012,8(1):1-7
Background
Biosynthesis of nanoparticles has received increasing attention due to the growing need to develop safe, time-effective and environmentally friendly technologies for nano-materials synthesis. This paper reports the one pot green synthesis of silver nanoparticles (AgNPs) using the leaf bud extract of a mangrove plant, Rhizophora mucronata and their antimicrobial effects against aquatic pathogens. Highly stable AgNPs were synthesized by treating the mangrove leaf bud extract with aqueous silver nitrate solution at 15?psi pressure and 121°C for 5 minutes.Results
The biosynthesized AgNPs were characterized by UV-visible spectrum, at 426?nm. The X-Ray Diffraction (XRD) pattern revealed the face-centered cubic geometry of AgNPs. Fourier Transform Infra Red (FTIR) spectroscopic analysis was carried out to identify the possible biomolecules responsible for biosynthesis of AgNPs from the leaf bud extract. The size and shape of the well-dispersed AgNPs were documented with the help of High Resolution Transmission Electron Microscopy (HRTEM) with a diameter ranged from 4 to 26?nm. However a maximum number of particles were observed at 4?nm in size. The antibacterial effects of AgNPs were studied against aquatic pathogens Proteus spp., Pseudomonas fluorescens and Flavobacterium spp., isolated from infected marine ornamental fish, Dascyllus trimaculatus.Conclusion
This study reveals that the biosynthesized AgNPs using the leaf bud extract of a mangrove plant (R. mucronata) were found equally potent to synthetic antibiotics. The size of the inhibition zone increases when the concentration of the AgNPs increased and varies according to species. 相似文献8.
Acceptor specificity of the human leukocyte alpha3 fucosyltransferase: role of FucT-VII in the generation of selectin ligands 总被引:2,自引:2,他引:0
Britten CJ; van den Eijnden DH; McDowell W; Kelly VA; Witham SJ; Edbrooke MR; Bird MI; de Vries T; Smithers N 《Glycobiology》1998,8(4):321-327
The alpha3 fucosyltransferase, FucT-VII, is one of the key
glycosyltransferases involved in the biosynthesis of the sialyl Lewis X
(sLex) antigen on human leukocytes. The sialyl Lewis X antigen
(NeuAcalpha(2-3)Galbeta(1-4)[Fucalpha(1-3)]GlcNAc-R) is an essential
component of the recruitment of leukocytes to sites of inflammation,
mediating the primary interaction between circulating leukocytes and
activated endothelium. In order to characterize the enzymatic properties of
the leukocyte alpha3 fucosyltransferase FucT-VII, the enzyme has been
expressed in Trichoplusia ni insect cells. The enzyme is capable of
synthesizing both sLexand sialyl-dimeric-Lexstructures in vitro , from
3'-sialyl-lacNAc and VIM-2 structures, respectively, with only low levels
of fucose transfer observed to neutral or 3'-sulfated acceptors. Studies
using fucosylated NeuAcalpha(2-3)-(Galbeta(1- 4)GlcNAc)3-Me acceptors
demonstrate that FucT-VII is able to synthesize both di-fucosylated and
tri-fucosylated structures from mono- fucosylated precursors, but
preferentially fucosylates the distal GlcNAc within a polylactosamine
chain. Furthermore, the rate of fucosylation of the internal GlcNAc
residues is reduced once fucose has been added to the distal GlcNAc. These
results indicate that FucT-VII is capable of generating complex selectin
ligands, in vitro , however the order of fucose addition to the lactosamine
chain affects the rate of selectin ligand synthesis.
相似文献
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The present study investigates the antidiabetogenic effects of Murraya koenigii (L.) Spr. and Ocimum tenuflorum L. on streptozotocin-induced diabetic Swiss mice. Treatment with extracts of M. koenigii (chloroform; MKC) and O. tenuflorum (aqueous; OTA) resulted in proper glucose utilization with an increase in liver glucose-6-phosphate dehydrogenase enzyme activity, and normal glycogenesis in hepatic and muscle tissues. Pancreatic and intestinal glucosidase inhibitory activity observed with MKC and OTA treatment indicated beneficial effects in reducing postprandial hyperglycemia with concomitant improvement in glucose metabolism. The glucosidase inhibition was prolonged, even after discontinuation of MKC and OTA treatment. Normalization of plasma insulin and C-peptide levels was observed in diabetic mice, indicating endogenous insulin secretion after treatment. The histochemical and immunohistochemical analysis of pancreatic islets suggests the role of MKC and OTA in pancreatic β-cell protection and the functional pancreatic islets that produce insulin. The study demonstrates the significance of MKC and OTA in glucosidase inhibition and islet protection in the murine diabetic model. These findings suggest the potential of the extracts in adjuvant therapy for the treatment of diabetes and the possible development of potential neutraceuticals. 相似文献