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The emerging outbreak of infectious diseases poses a challenge and threatens human survival. The indiscriminate use and drying pipelines of antibiotic arsenals have led to the alarming rise of drug-resistant pathogens, projecting a serious concern. The rising antimicrobial resistance and redundancy of antibiotic discovery platforms (ADPs) have highlighted the growing concern to discover new antibiotics, necessitating exploring natural products as effective alternatives to counter drug resistance. Recently, plants have been extensively investigated in search of the "phytotherapeutics", attributed to their potential efficacy and tackling the majority of the drug-resistant mechanisms, including biofilms, efflux pumps, cell communication, and membrane proteins. However, major challenges in geographical fluctuations, low plant concentration, and over-harvestation of natural resources restrict availability and complete utilization of phyto-therapeutics as antimicrobials. Recent advances in scientific interventions have been instrumental in producing novel antimicrobials via metabolic engineering approaches in plant systems. The progress in plant genome editing, pathway reconstitution, and expression has defined new paradigms in the successful production of antimicrobials in the post-antibiotic era. The thematic review discusses the existing and emerging significance of phytotherapeutics in tackling antimicrobial resistance and employing metabolic engineering approaches. The prevailing scenario of antimicrobial resistance and the mechanisms, the traditional and modern drug-discovery approaches in addressing antimicrobial resistance, emphasizing advances in metabolic engineering approaches for antimicrobial production, and the plausible solutions for tackling drug-resistant pathogens, forms the key theme of the article., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The increased multidrug resistance in Acinetobacter baumannii (A. baumannii) to the present-day known antibiotics has stimulated academic and industrial efforts globally for the development of novel antibacterial agents. Natural compounds as potential drug leads are gaining significant attention due to their less toxic and more tolerant nature. In the current study, the natural product-based compounds were explored as probable inhibitors of UDP-N-acetylmuramoyl-L-alanine:D-glutamate (MurD) ligase from A.baumannii ( Ab MurD) to provide a new class of drug leads. The prepared natural library of 3,16,714 compounds from ZINC database was screened into the active site of Ab MurD using in silico high-throughput virtual screening which resulted in 100 compounds having high binding affinities. Further screening through flexible molecular docking yielded four potential compounds selected on the basis of estimated binding affinity (ΔG) and favorable protein-ligand interactions. MD simulation of these four compounds under physiological conditions and free binding energy calculations using MM/PBSA (molecular mechanics with Poisson- Boltzmann and surface area solvation) approach revealed three compounds ZINC08879777, ZINC30726863, and ZINC95486217 as potential binders of Ab MurD. The calculated physicochemical and ADME properties of these compounds revealed that they can be exploited and modified to improve their binding affinity with the enzyme. Two compounds were purchased and tested against bacterial cell cultures of A. baumannii, Salmonella Typhi, and Staphylococcus aureus to determine their broad-spectrum antibacterial activity. The results suggest that the identified compounds can be exploited as potential herbal leads to target both Gram-positive and Gram-negative pathogens. Communicated by Ramaswamy H. Sarma.

Plant-endophyte associations represent an inexhaustible source of novel metabolites, exhibiting significance in environment, agriculture and pharmaceutical perspectives. The global outbreak of life-threatening diseases necessitates a need for a more targeted approach through efficient drug-discovery programs. In recent times, endophytes as "bio-factories" have been extensively explored for the production of novel bioactive metabolites demonstrating therapeutic properties. Resources in computational biology co-integrated with combinational chemistry have made significant contributions in this field, aiding in discovery and screening of potential "drug-like" molecules from endophytes. The review provides a meta-analysis of bioactive metabolite production from endophytes, extensively discussing the bio-prospection of natural products for pharmaceutical applications. In light of emerging importance of endophytes as anti-infective agents, an exploration of the pharmaceutical design of novel chemical entities and analogues has enabled efficient and cost-effective drug discovery programs. However, bottlenecks in endophyte biology and research require a better understanding of endophyte dynamics and mechanism of bioactive metabolite production towards a sustainable drug discovery program., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

DNA Gyrase is a type II topoisomerase that utilizes the energy of ATP hydrolysis for introducing negative supercoils in DNA. The protein comprises two subunits GyrA and GyrB that form a GyrA 2 GyrB 2 heterotetramer. GyrB subunit contains the N-terminal domain (GBNTD) for ATPase activity and the C-terminal domain (GBCTD) for interaction with GyrA and DNA. Earlier structural studies have revealed three different conformational states for GBNTD during ATP hydrolysis defined as open, semi-open, and closed. Here we report, the three-dimensional structure of a new transient closed conformation of GBNTD from Salmonella Typhi (StGBNTD) at 1.94 Å resolution. Based on the structural analysis of this transient closed conformation, we propose the role of protein in the mechanism of ATP hydrolysis. We further explored the effect of pH on ATPase activity and structural stability of the GBNTD using CD and fluorescence spectroscopy at varying pH environment. Kinetic parameters obtained from the ATPase assay were correlated with its secondary and tertiary structure at their respective pH environment. The protein possessed maximum ATPase activity and structural stability at optimum pH 8. At acidic pH, a remarkable decrease in both enzymatic activity and structural stability was observed whereas at alkaline pH there was no significant change. The structural analysis of StGBNTD reveals the role of polar interactions in stabilizing the overall dimeric conformation of the protein., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Crystallographic and electronic structures of phase pure ternary solid solutions of Ni 1- x Co x O ( x = 0 to 1) have been studied using XRD, EXAFS and XAS measurements. The lattice parameter of the cubic rock-salt (RS) Ni 1- x Co x O solid solutions increases linearly with increasing Co content and follows Vegard's law, in the complete composition range. A linear increase in the bond lengths (Ni/Co-O, Ni-Ni and Ni-Co) with " x ", closely following the bond lengths determined from virtual crystal approximation (VCA), is observed, which implies that there is only a minimal local distortion of the lattice in the mixed crystal. The optical gap of the ternary solid solution determined from diffuse reflectivity measurements shows neither a linear variation with Co composition nor bowing, as observed in many ternary semiconductors. This trend in the variation of optical gaps is explained by probing the conduction band using XAS at the O K-edge. We have observed that the variation in the onset energy of the conduction band edge with " x " is very similar to the variation in the optical gap with " x ", thus clearly indicating the dominant role played by the conduction band position in determining the optical gap. The variation in the intensities of the pre-edge peak in the XANES spectra measured at Ni and Co K-edges, and the L 1/2 peak in XAS spectra measured at Ni and Co L-edges, is found to depend on the unoccupied O 2p-metal-(Ni/Co) 3d hybridized states and the bond lengths., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Diabetes accounts for high mortality rate worldwide affecting million of lives annually. Global prevalence of diabetes and its rising frequency makes it a key area of research in drug discovery programs. The research article describes the development of quantitative structure activity relationship model against PPARγ, a promising drug target for diabetes. Multiple linear regression approach was adopted for statistical model development and the QSAR relationship suggested the regression coefficient (r2) of 0.84 and the cross validation coefficient (rCV2) of 0.77. Further, the study suggested that chemical descriptors viz., dipole moment, electron affinity, dielectric energy, secondary amine group count and LogP correlated well with the activity. The docking studies showed that most active gymnemic acid analogues viz., gymnemasin D and gymnemic acid VII possess higher binding affinity to PPARγ. QSAR and ADMET studies based other predicted active gymnemc acid analogues were gymnemic acid I, gymnemic acid II, gymnemic acid III, gymnemic acid VIII, gymnemic acid X, gymnemic acid XII, gymnemic acid XIV, gymnemic acid XVIII and gymnemoside W2. Predicted activity results of three query compounds were found comparable to experimental in vivo data. Oral bioavailability of these active analogues is still a limiting factor and therefore further lead optimization required. Also, such study would be of great help in active pharmacophore discovery and lead optimization, and offering new insights into therapeutics for diabetes mellitus.