Repurposing ebselen for Treatment of Multidrug-Resistant Staphylococcal Infections

Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections

Repurposing Celecoxib as a Topical Antimicrobial Agent

There is an urgent need for new antibiotics and alternative strategies to combat multidrug-resistant bacterial pathogens, which are a growing clinical issue. Repurposing existing approved drugs with known pharmacology and toxicology is an alternative strategy to accelerate antimicrobial research and development. In this study, we show that celecoxib, a marketed inhibitor of cyclooxygenase-2, exhibits broad-spectrum antimicrobial activity against Gram-positive pathogens from a variety of genera, including Staphylococcus, Streptococcus, Listeria, Bacillus, and Mycobacterium, but not against Gram-negative pathogens. However, celecoxib is active against all of the Gram-negative bacteria tested, including strains of, Acinetobacter, and Pseudomonas, when their intrinsic resistance is artificially compromised by outer membrane permeabilizing agents such as colistin. The effect of celecoxib on incorporation of radioactive precursors into macromolecules in Staphylococcus aureus was examined. The primary antimicrobial mechanism of action of celecoxib was the dose-dependent inhibition of RNA, DNA, and protein synthesis. Further, we demonstrate the in vivo efficacy of celecoxib in a methicillin-resistant S. aureus (MRSA) infected Caenorhabditis elegans whole animal model. Topical application of celecoxib (1 and 2%) significantly reduced the mean bacterial count in a mouse model of MRSA skin infection. Further, celecoxib decreased the levels of all inflammatory cytokines tested, including tumor necrosis factor-α, interleukin-6, interleukin-1 beta, and monocyte chemo attractant protein-1 in wounds caused by MRSA infection. Celecoxib also exhibited synergy with many conventional antimicrobials when tested against four clinical isolates of S. aureus. Collectively, these results demonstrate that celecoxib alone, or in combination with traditional antimicrobials, has a potential to use as a topical drug for the treatment of bacterial skin infections

Repurposing clinical molecule ebselen to combat drug resistant pathogens

Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90) were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillinresistant S. aureus (MRSA) in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated. © 2015 Thangamani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Impact of design characteristics of daylight elements to creating healthy internal environment for school buildings evaluation the status of schools in Mosul city

The current research deals with impact of design characteristics that creates attractive and healthy internal environments for school building , as one of the most important issue on evaluating random position of local school building in Mosul city .Because they are describes as limited efficiency of educational performance and lake of healthy feature . This paper addresses the issue of daylight effects factors that supports efficiency of interiors in school building by using specific quality of design characteristics that related building composition in one hand , and elements of classes daylight in the other. The objective of this paper is to determine the key design properties affecting to achieves healthy spatial environment , which are related on two main daylight factors :solarization average for building at all ,and homogeneity of daylight at work surface in classroom space . The study employed (Velux Daylight Visualizer – 2012) in deign research methodology to evaluate three school building types that used in Mosul city .Finding of this study confirmed that the deign properties related two factors of daylight have effective role in creating healthy interiors and increase educational productivity. The result of this study are useful reference for architects ,planner ,landscape ,and researcher in this field , the municipality of Mosul

A Smart Context-Aware Hazard Attention System to Help People with Peripheral Vision Loss

Peripheral vision loss results in the inability to detect objects in the peripheral visual field which affects the ability to evaluate and avoid potential hazards. A different number of assistive navigation systems have been developed to help people with vision impairments using wearable and portable devices. Most of these systems are designed to search for obstacles and provide safe navigation paths for visually impaired people without any prioritisation of the degree of danger for each hazard. This paper presents a new context-aware hybrid (indoor/outdoor) hazard classification assistive technology to help people with peripheral vision loss in their navigation using computer-enabled smart glasses equipped with a wide-angle camera. Our proposed system augments users’ existing healthy vision with suitable, meaningful and smart notifications to attract the user’s attention to possible obstructions or hazards in their peripheral field of view. A deep learning object detector is implemented to recognise static and moving objects in real time. After detecting the objects, a Kalman Filter multi-object tracker is used to track these objects over time to determine the motion model. For each tracked object, its motion model represents its way of moving around the user. Motion features are extracted while the object is still in the user’s field of vision. These features are then used to quantify the danger using five predefined hazard classes using a neural network-based classifier. The classification performance is tested on both publicly available and private datasets and the system shows promising results with up to 90% True Positive Rate (TPR) associated with as low as 7% False Positive Rate (FPR), 13% False Negative Rate (FNR) and an average testing Mean Square Error (MSE) of 8.8%. The provided hazard type is then translated into a smart notification to increase the user’s cognitive perception using the healthy vision within the visual field. A participant study was conducted with a group of patients with different visual field defects to explore their feedback about the proposed system and the notification generation stage. The real-world outdoor evaluation of human subjects is planned to be performed in our near future work