Methicillin-Resistant Staphylococcus aureus Infection and its Health Perspective: A Review.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a potential threat globally since it is associated with high morbidity and mortality. In addition, the ability of MRSA to develop resistance and adapt to various environments makes it exceptional from other bacterial strains. Effective management is best determined by the site of infection. OBJECTIVES: This study aims to summarize and assess the epidemiology of MRSA, resistance, detection of MRSA in humans, animals, and food products, treatment employed, and combination therapy. METHODS: For the present review, we collected data from PubMed, Embase, Web of Science, BioMed Central, Medline, Encyclopedia of Life Sciences, Scopus, Cochrane Library, and ScienceDirect that report the epidemiology of MRSA, drug resistance in MRSA, spread of MRSA infection, diagnosis of infection, existing and emerging remedies of MRSA infections. Collected data were analyzed and represented in this article with the help of Figures and Tables. RESULTS: S. aureus resistance to vancomycin is because of genetic adaptation and also due to the widespread and indiscriminate use of antibiotics in the treatment of MRSA infection. Specifically, infections related to vancomycin-resistant S. aureus are life-threatening and difficult to treat. MRSA epidemiology with the recognition of community-acquired-MRSA transmission between livestock and humans is also reported and is alarming. Multiple studies suggested that early detection of MRSA colonization and elimination of carriage can help reduce the risk of subsequent infection. Specifically, PCR-based screening from different body sites offers the highest overall sensitivity for the detection of MRSA carriage. CONCLUSION: Screening novel mutants and methods of transmission in each environment will assist in managing MRSA. Further, effective MRSA control in all clinical setups is required with the avoidance of uncontrolled antibiotic usage.

Virtual high throughput screening of natural peptides against ErbB1 and ErbB2 to identify potential inhibitors for cancer chemotherapy.

Human epidermal growth factor receptors (EGFR), namely ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4, the trans-membrane family of tyrosine kinase receptors, are overexpressed in many types of cancers. These receptors play an important role in cell proliferation, differentiation, invasion, metastasis and angiogenesis including unregulated activation of cancer cells. Overexpression of ErbB1 and ErbB2 that occurs in several types of cancers is associated with poor prognosis leading to resistance to ErbB1-directed therapies. In this connection, promising strategy to overcome the disadvantages of the existing chemotherapeutic drugs is the use of short peptides as anticancer agents. In the present study, we have performed virtual high throughput screening of natural peptides against ErbB1 and ErbB2 to identify potential dual inhibitors and identified five inhibitors based on their binding affinities, ADMET analysis, MD simulation studies and calculation of free energy of binding. These natural peptides could be further exploited for developing drugs for treating cancer.Communicated by Ramaswamy H. Sarma.

Neurotrophin mimetics and tropomyosin kinase receptors: a futuristic pharmacological tool for Parkinson's.

Parkinson's disease is a complex age-related progressive dopaminergic neurodegenerative disease consistently viewed as a disorder of movement and is characterized by its cardinal motor symptoms. While the motor symptoms and its clinical manifestations are attributed to the nigral dopaminergic neuronal death and basal ganglia dysfunction, studies have subsequently proven that the non-dopaminergic neurons in various brain regions are also additionally involved with the disease progression. Thus, it is now well accepted that the involvement of various neurotransmitters and other ligands accounts for the non-motor symptoms (NMS) associated with the Parkinson's disease. Consequently, this has demonstrated to possess remarkable clinical concerns to the patients in terms of various disability, such impaired to compromised quality of life and increased risk of morbidity and mortality. Currently, available pharmacological, non-pharmacological, and surgical therapeutic strategies neither prevent, arrest, nor reverse the nigral dopaminergic neurodegeneration. Thus, there is an imminent medical necessity to increase patient's quality of life and survival, which in turn decreases the incidence and prevalence of the NMS. The current research article reviews the potential direct involvement of neurotrophin and its mimetics to target and modulate neurotrophin-mediated signal transduction pathways to enlighten a new and novel therapeutic strategy along with the pre-existing treatments for Parkinson's disease and other neurological/neurodegenerative disorders which are associated with the downregulation of neurotrophins.

In-silico docking and molecular dynamic introspective study of multiple targets of AChE with Rivastigmine and NMDA receptors with Riluzole for Alzheimer's disease.

The present study was initiated with PDB selection and validation where 11 acetylcholinesterase (AChE) and 4 N-methyl-D-aspartate receptor (NMDAR) proteins were considered for docking with Rivastigmine and Riluzole respectively. Out of the 15 proteins, selected significant binding was observed for AChE, with 5FPQ, and NMDA receptors with 5I2K. Molecular docking studies of 5FPQ/Rivastigmine complex displayed a binding score of -8.6 kcal/mol, and the predicted inhibitory concentration (Ki) was found to be 31 nM, whereas the 5I2K/Riluzole complex showed a binding score of -9.6 kcal/mol, with an inhibitory concentration (Ki) of 21 nM. Riluzole in complex with 5I2K formed predominant π-π stacking interactions with Tyr144, pi-alkyl interaction with Pro129, and conventional hydrogen bond with Phe130. In contrast, Rivastigmine in a complex with 5FPQ formed a hydrogen bond with Gln413 and pi-alkyl with Pro537. Molecular dynamics simulation study of both complexes 5FPQ/Rivastigmine and 5I2K/Riluzole exhibited stable RMSD, RMSF, Rg, and significant numbers of hydrogen bonds. From free energy landscape (FEL) analysis both complexes were observed to achieve global minima. Overall, molecular docking and MD simulation with subsequent binding free energies studies (MM-PBSA) elucidate the binding conformations and stability of these reprogrammed drugs in the AChE and NMDAR targets. From these in-silico predictions, it can be suggested that both Rivastigmine and Riluzole combination may provide better insights as a starting point combination therapy for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

Ceftriaxone induces glial EAAT-2 promotor region via NF-kB conformational changes: An interaction analysis using HADDOCK.

Excitotoxicity, depletion of energy metabolites, and ionic imbalance are the major factors involved in neurodegeneration mediated through excitatory amino acid transporter-2 (EAAT-2) dysfunction in ischemic insult. Recent studies have revealed that ceftriaxone expresses EAAT-2 via nuclear transcription factor kappa-B (NF-kB) signaling pathway, stimulation of EAAT-2 expression in the ischemic, and excitotoxic conditions that could provide potential benefits to control neurodegeneration. In this study, we have predicted the in silico model for interaction between NF-kB and EAAT-2 promoter region to rule out the conformational changes for the expression of EAAT-2 protein. Using homology-built model of NF-kB, we identified ceftriaxone-induced conformational changes in gene locus -272 of DNA where NF-kB binding with EAAT-2 promoter region through protein-DNA docking calculation. The interaction profile and conformational dynamics occurred between ceftriaxone predocked and postdocked conformations of NF-kB with DNA employing HADDOCK 2.2 web server followed by 250 ns long all atom explicit solvent molecular dynamics simulations. Both the protein and DNA exhibited modest conformational changes with respect to HADDOCK score, energy terms (desolvation energy [Edesolv ]), van der waal energy (Evdw ), electrostatic energy (Eelec ), restraints energy (Eair ), buried surface area, root mean square deviation, RMSF, radius of gyration, total hydrogen bonds when ceftriaxone pre- and postdocked NF-kB conformations were bound to DNA. Hence, the conformational changes in the C-terminal domain could be the reason for EAAT-2 expression through ceftriaxone specific binding pocket of -272 of DNA.

GlmU Inhibitors as Promising Antibacterial Agents: A Review.

Bacterial infections are a major cause of mortality and morbidity in humans throughout the world. Infections due to resistant bacterial strains such as methicillin-resistant Staphyloccocusaureus vancomycin, resistant Enterococci, Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium are alarming. Hence the development of new antibacterial agents, which act via a novel mechanism of action, became a priority in antibacterial research. One such approach to overcome bacterial resistance is to target novel protein and develop antibacterial agents that act via different mechanisms of action. Bacterial GlmU is one such bifunctional enzyme that catalyzes the two consecutive reactions during the biosynthesis of uridine 5'-diphospho-Nacetylglucosamine, an essential precursor for the biosynthesis of bacterial cell wall peptidoglycan. This enzyme comprises two distinct active sites; acetyltransferase and uridyltransferase and both these active sites act independently during catalytic reactions. GlmU is considered an attractive target for the design and development of newer antibacterial agents due to its important role in bacterial cell wall synthesis and the absence of comparable enzymes in humans. Availability of three dimensions X-crystallographic structures of GlmU and their known catalytic mechanism from different bacterial strains have instigated research efforts for the development of novel antibacterial agents. Several GlmU inhibitors belonging to different chemical classes like 2- phenylbenzofuran derivative, quinazolines, aminoquinazolines, sulfonamides, arylsulfonamide, D-glucopyranoside 6-phosphates, terreic acid, iodoacetamide, N-ethyl maleimide, and Nethylmaleimide etc., have been reported in the literature. In the present review, we present an update on GlmU inhibitors and their associated antibacterial activities. This review may be useful for the design and development of novel GlmU inhibitors with potent antibacterial activity.