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Multiple mutations in the β subunit of the RNA polymerase (rpoβ) of Mycobacterium tuberculosis (Mtb) are the primary cause of resistance to rifamycin (RIF). In the present study, bifidobacterial rpoβ sequences were analyzed to characterize the mutations that contribute to the development of intrinsic resistance to RIF, isoniazid, streptomycin and pyrazinamide. Sequence variations, which mapped to cassettes 1 and 2 of the rpoβ pocket, are also found in multidrug-resistant Mtb (MDR Mtb ). Growth curves in the presence of osmolytes and different concentrations of RIF showed that the bacteria adapted rapidly by shortening the growth curve lag time. Insight into the adapted rpoβ DNA sequences revealed that B. adolescentis harbored mutations both in the RIF pocket and in regions outside the pocket. The minimum inhibitory concentrations (MICs) and mutant prevention concentrations (MPCs) indicated that B. longum, B. adolescentis and B. animalis are resistant to antitubercular drugs. 3D-homology modeling and binding interaction studies using computational docking suggested that mutants had reduced binding affinity towards RIF. RIF-exposed/resistant bacteria exhibited variant protein profiles along with morphological differences, such as elongated and branched cells, surface conversion from rough to smooth, and formation of a concentrating ring.

The enzymes decaprenylphosphoryl-β-D-ribose oxidase (DprE1) and decaprenylphosphoryl-β-D-ribose-2-epimerase (DprE2) catalyze epimerization of decaprenylphosporyl ribose (DPR) todecaprenylphosporyl arabinose (DPA) and are critical for the survival of Mtb. Crystal structures of DprE1 so far reported display significant disordered regions and no structural information is known for DprE2. We used homology modeling, protein threading, molecular docking and dynamics studies to investigate the structural and dynamic features of Mtb DprE1 and DprE2 and DprE1-DprE2 complex. A three-dimensional model for DprE2 was generated using the threading approach coupled with ab initio modeling. A 50 ns simulation of DprE1 and DprE2 revealed the overall stability of the structures. Principal Component Analysis (PCA) demonstrated the convergence of sampling in both DprE1 and DprE2. In DprE1, residues in the 269-330 area showed considerable fluctuation in agreement with the regions of disorder observed in the reported crystal structures. In DprE2, large fluctuations were detected in residues 95-113, 146-157, and 197-226. The study combined docking and MD simulation studies to map and characterize the key residues involved in DprE1-DprE2 interaction. A 60 ns MD simulation for DprE1-DprE2 complex was also performed. Analysis of data revealed that the docked complex is stabilized by H-bonding, hydrophobic and ionic interactions. The key residues of DprE1 involved in DprE1-DprE2 interactions belong to the disordered region. We also examined the docked complex of DprE1-BTZ043 to investigate the binding pocket of DprE1 and its interactions with the inhibitor BTZ043. In summary, we hypothesize that DprE1-DprE2 interaction is crucial for the synthesis of DPA and DprE1-DprE2 complex may be a new therapeutic target amenable to pharmacological validation. The findings have important implications in tuberculosis (TB) drug discovery and will facilitate drug development efforts against TB.

Research into the biological role of the Ca 2+ -releasing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate) has been hampered by a lack of chemical probes. To find new chemical probes for exploring NAADP signaling, we turned to virtual screening, which can evaluate millions of molecules rapidly and inexpensively. We used NAADP as the query ligand to screen the chemical library ZINC for compounds with similar three-dimensional shape and electrostatic properties. We tested the top-ranking hits in a sea urchin egg bioassay and found that one hit, Ned-19, blocks NAADP signaling at nanomolar concentrations. In intact cells, Ned-19 blocked NAADP signaling and fluorescently labeled NAADP receptors. Moreover, we show the utility of Ned-19 as a chemical probe by using it to demonstrate that NAADP is a key causal link between glucose sensing and Ca 2+ increases in mouse pancreatic beta cells.

The druggability of epigenetic targets has prompted researchers to develop small-molecule therapeutics. However, no systematic assessment has ever been done to investigate the chemical space of epigenetic modulators. Herein, we report a comprehensive chemoinformatic analysis of epigenetic ligands from EpiDBase, HEMD, ChEMBL and PubChem databases. Nearly, 0.45 × 10 ligands were analyzed for assay interference compounds, target profiling, drug-like properties and hit prioritization. After eliminating approximately 96,000 problematic compounds, the remaining 0.36 × 10 compounds were studied for their physicochemical distributions, principal component analysis and hit prioritization. More than 30% of assay interference compounds were determined for many proteins. This systematic assessment of epigenetic ligands will help in the enrichment of screening libraries with high-quality compounds and thus, the generation of efficacious drug candidates.

A thorough, accessible, and general overview of chemosensors Providing a comprehensive overview of chemosensors—organic molecules designed to bind and sense small molecules or metal ions—and their applications, Chemosensors: Principles, Strategies, and Applications is an accessible one-stop resource for analysts, clinicians, and graduate students studying advanced chemistry and chemosensing. Chemosensors function on a molecular level, generating a signal upon binding. The book reviews their synthesis, design, and applications for detecting biological and organic molecules as well as metal ions. The text highlights applications in drug discovery and catalyses that have not been well covered elsewhere. Covering such topics as molecular recognition, detection methods, design strategies, and important biological issues, the book is broken into four sections that examine intermolecular interactions, strategies in sensor design, detection methods, and case studies in metal, saccharide, and amino acid sensing. An indispensable source of information for chemical and biomedical experts using sensors, Chemosensors includes case studies to make the material both accessible and understandable to chemists of all backgrounds.

The enzymes decaprenylphosphoryl- beta -D-ribose oxidase (DprE1) and decaprenylphosphoryl- beta -D-ribose-2-epimerase(DprE2) catalyze epimerization of decaprenylphosporyl ribose (DPR) todecaprenylphosporyl arabinose (DPA) and are critical for the survival of Mtb. Crystal structures of DprE1 so far reported display significant disordered regions and no structural information is known for DprE2. We used homology modeling, protein threading, molecular docking and dynamics studies to investigate the structural and dynamic features of Mtb DprE1 and DprE2 and DprE1-DprE2 complex. A three-dimensional model for DprE2 was generated using the threading approach coupled with ab initio modeling. A 50 ns simulation of DprE1 and DprE2 revealed the overall stability of the structures. Principal Component Analysis (PCA) demonstrated the convergence of sampling in both DprE1 and DprE2. In DprE1, residues in the 269-330 area showed considerable fluctuation in agreement with the regions of disorder observed in the reported crystal structures. In DprE2, large fluctuations were detected in residues 95-113, 146-157, and 197-226. The study combined docking and MD simulation studies to map and characterize the key residues involved in DprE1-DprE2 interaction. A 60 ns MD simulation for DprE1-DprE2 complex was also performed. Analysis of data revealed that the docked complex is stabilized by H-bonding, hydrophobic and ionic interactions. The key residues of DprE1 involved in DprE1-DprE2 interactions belong to the disordered region. We also examined the docked complex of DprE1-BTZ043 to investigate the binding pocket of DprE1 and its interactions with the inhibitor BTZ043. In summary, we hypothesize that DprE1-DprE2 interaction is crucial for the synthesis of DPA and DprE1-DprE2 complex may be a new therapeutic target amenable to pharmacological validation. The findings have important implications in tuberculosis (TB) drug discovery and will facilitate drug development efforts against TB.

Microdamage accumulation leads to reduced bone strength and fracture. Intact, damaged and Rose Bengal stained cortical bone specimens were studied using SEM and EDXA imaging. SEM coupled with EDXA studies showed selective labelling of surface damage due to binding of dye at free lattice sites. A series of novel iodinated X-ray contrast agent were synthesised. These agents demonstrated excellent stability, water solubility and lack of atropisomerism. Preliminary imaging studies, using cone-beam μ-CT, demonstrated their ability to provide visible contrast in the solid state on bone surfaces.

This chapter contains sections titled: Introduction Basic Principles of Fluorescence Sensing: An Introduction Basic Principles of Photochemistry Examples of Florescence Detection Strategies and Principles Conclusion References