Discovery of antivirulence agents against methicillin-resistant staphylococcus aureus

Antivirulence agents inhibit the production of disease-causing virulence factors but are neither bacteriostatic nor bactericidal. Antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA) strain USA300, the most widespread community-associated MRSA strain in the United States, were discovered by virtual screening against the response regulator AgrA, which acts as a transcription factor for the expression of several of the most prominent S. aureus toxins and virulence factors involved in pathogenesis. Virtual screening was followed by similarity searches in the databases of commercial vendors. The small-molecule compounds discovered inhibit the production of the toxins alpha-hemolysin and phenol-soluble modulin α in a dose-dependent manner without inhibiting bacterial growth. These antivirulence agents are small-molecule biaryl compounds in which the aromatic rings either are fused or are separated by a short linker. One of these compounds is the FDA-approved nonsteroidal anti-inflammatory drug diflunisal. This represents a new use for an old drug. Antivirulence agents might be useful in prophylaxis and as adjuvants in antibiotic therapy for MRSA infections

Combinatorial Synthesis and in Vitro Evaluation of a Biaryl Hydroxyketone Library as Antivirulence Agents against MRSA

Antibiotic resistance coupled with decreased development of new antibiotics necessitates the search for novel antibacterial agents. Antivirulence agents offer an alternative to conventional antibiotics. In this work, we report on a family of small-molecule antivirulence agents against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), the most widespread bacterial pathogen. Structure–activity relationship studies led to the development of a concise synthesis of a 148-member biarylhydroxyketone library. An acylation bond-forming process afforded resorcinols (<b>1</b>) and aryloxy acetonitriles (<b>2</b>) as synthons. A Lewis-acid-activated Friedel–Crafts’ acylation step involving a nitrile functionality of <b>2</b> by ZnCl₂, followed by nucleophilic attack by <b>1</b> was executed to obtain biaryl hydroxyketones in excellent yields. A large number of products crystallized. This strategy affords a range of biarylhydroxyketones in a single step. This is the first collective synthetic study documenting access to this class of compounds through a single synthetic operation. In vitro efficacy of compounds in this library was evaluated by a rabbit erythrocyte hemolysis assay. The most efficacious compound, <b>4f-12</b>, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound

Combinatorial Synthesis and in Vitro Evaluation of a Biaryl Hydroxyketone Library as Antivirulence Agents against MRSA

Antibiotic resistance coupled with decreased development of new antibiotics necessitates the search for novel antibacterial agents. Antivirulence agents offer an alternative to conventional antibiotics. In this work, we report on a family of small-molecule antivirulence agents against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), the most widespread bacterial pathogen. Structure–activity relationship studies led to the development of a concise synthesis of a 148-member biarylhydroxyketone library. An acylation bond-forming process afforded resorcinols (<b>1</b>) and aryloxy acetonitriles (<b>2</b>) as synthons. A Lewis-acid-activated Friedel–Crafts’ acylation step involving a nitrile functionality of <b>2</b> by ZnCl₂, followed by nucleophilic attack by <b>1</b> was executed to obtain biaryl hydroxyketones in excellent yields. A large number of products crystallized. This strategy affords a range of biarylhydroxyketones in a single step. This is the first collective synthetic study documenting access to this class of compounds through a single synthetic operation. In vitro efficacy of compounds in this library was evaluated by a rabbit erythrocyte hemolysis assay. The most efficacious compound, <b>4f-12</b>, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound

Prolonged prevention of retinal degeneration with retinylamine loaded nanoparticles.

Retinal degeneration impairs the vision of millions in all age groups worldwide. Increasing evidence suggests that the etiology of many retinal degenerative diseases is associated with impairment in biochemical reactions involved in the visual cycle, a metabolic pathway responsible for regeneration of the visual chromophore (11-cis-retinal). Inefficient clearance of toxic retinoid metabolites, especially all-trans-retinal, is considered responsible for photoreceptor cytotoxicity. Primary amines, including retinylamine, are effective in lowing the concentration of all-trans-retinal within the retina and thus prevent retina degeneration in mouse models of human retinopathies. Here we achieved prolonged prevention of retinal degeneration by controlled delivery of retinylamine to the eye from polylactic acid nanoparticles in Abca4(-/-)Rdh8(-/-) (DKO) mice, an animal model of Stargardt disease/age-related macular degeneration. Subcutaneous administration of the nanoparticles containing retinylamine provided a constant supply of the drug to the eye for about a week and resulted in effective prolonged prevention of light-induced retinal degeneration in DKO mice. Retinylamine nanoparticles hold promise for prolonged prophylactic treatment of human retinal degenerative diseases, including Stargardt disease and age-related macular degeneration

Manganese-Enhanced MRI for Preclinical Evaluation of Retinal Degeneration Treatments

PURPOSE: Apply manganese-enhanced magnetic resonance imaging (MEMRI) to assess ion channel activity and structure of retinas from mice subject to light-induced retinal degeneration treated with prophylactic agents. METHODS: Abca4(−/−)Rdh8(−/−) double knockout mice with and without prophylactic retinylamine (Ret-NH(2)) treatment were illuminated with strong light. Manganese-enhanced MRI was used to image the retina 2 hours after intravitreous injection of MnCl(2) into one eye. Contrast-enhanced MRIs of the retina and vitreous humor in each experimental group were assessed and correlated with the treatment. Findings were compared with standard structural and functional assessments of the retina by optical coherence tomography (OCT), histology, and electroretinography (ERG). RESULTS: Manganese-enhanced MRI contrast in the retina was high in nonilluminated and illuminated Ret-NH(2)–treated mice, whereas no enhancement was evident in the retina of the light-illuminated mice without Ret-NH(2) treatment (P < 0.0005). A relatively high signal enhancement was also observed in the vitreous humor of mice treated with Ret-NH(2). Strong MEMRI signal enhancement in the retinas of mice treated with retinylamine was correlated with their structural integrity and function evidenced by OCT, histology, and a strong ERG light response. CONCLUSIONS: Manganese-enhanced MRI has the potential to assess the response of the retina to prophylactic treatment based on the measurement of ion channel activity. This approach could be used as a complementary tool in preclinical development of new prophylactic therapies for retinopathies

Combinatorial Synthesis and in Vitro Evaluation of a Biaryl Hydroxyketone Library as Antivirulence Agents against MRSA

Antibiotic resistance coupled with decreased development of new antibiotics necessitates the search for novel antibacterial agents. Antivirulence agents offer an alternative to conventional antibiotics. In this work, we report on a family of small-molecule antivirulence agents against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), the most widespread bacterial pathogen. Structure–activity relationship studies led to the development of a concise synthesis of a 148-member biarylhydroxyketone library. An acylation bond-forming process afforded resorcinols (<b>1</b>) and aryloxy acetonitriles (<b>2</b>) as synthons. A Lewis-acid-activated Friedel–Crafts’ acylation step involving a nitrile functionality of <b>2</b> by ZnCl₂, followed by nucleophilic attack by <b>1</b> was executed to obtain biaryl hydroxyketones in excellent yields. A large number of products crystallized. This strategy affords a range of biarylhydroxyketones in a single step. This is the first collective synthetic study documenting access to this class of compounds through a single synthetic operation. In vitro efficacy of compounds in this library was evaluated by a rabbit erythrocyte hemolysis assay. The most efficacious compound, <b>4f-12</b>, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound

Relationships of weight perceptions with weight control related behaviors among Chinese children and adolescents: A school-based study in Zhejiang Province.

ObjectivesWeight perceptions have been implicated in weight control related behaviors among children and adolescents, yet studies in mainland China are scarce. We examined the associations of self-perceived weight status and weight misperception with weight control related behaviors in Chinese middle and high school students.MethodsWe used cross-sectional data from the 2017 Zhejiang Youth Risk Behavior Survey which that included 17,359 Chinese students, with 8,616 boys and 8,743 girls. Perceived weight status, as well as height, weight and weight control related behaviors information was collected via a self-reported questionnaire. Odds ratios (ORs) with 95% confidence intervals (CIs) calculated by multinomial logistic regression were used to assess the relationships between weight perceptions and weight control related behaviors.ResultsAmong the 17,359 students aged 9 to 18 years, the mean (SD) age was 15.72 (1.64) years. Overall, 34.19% of children and adolescents perceived themselves as overweight and the prevalence of weight misperception was 45.44%, with 35.54% overestimation and 9.90% underestimation. Children and adolescents perceiving themselves as overweight were more likely to have weight control behaviors, with OR was 2.60 (95% CI: 2.39-2.83) for weight control attempt, 2.48 (2.28-2.70) for exercising, 2.85 (2.60-3.11) for dieting, 2.01 (1.51-2.68) for taking laxatives, 2.09 (1.67-2.02) for taking diet pills, and 2.39 (1.94-2.94) for fasting, respectively, compared to those with right weight status. Among children and adolescents with overestimating weight status, the OR was 2.40 (2.22-2.59), 2.50 (2.31-2.70), 2.85 (2.61-3.11), 1.81 (1.39-2.37), 2.20 (1.77-2.74), and 2.16 (1.77-2.63) for weight control attempt, exercising, dieting, taking laxatives, taking diet pills, and fasting, relative to those with accurate weight perception.ConclusionsSelf-perceived overweight and weight misperception are prevalent in Chinese children and adolescents, and positively associated with weight control related behaviors

Unique antitumor property of the Mg-Ca-Sr alloys with addition of Zn

In clinical practice, tumor recurrence and metastasis after orthopedic prosthesis implantation is an intensely troublesome matter. Therefore, to develop implant materials with antitumor property is extremely necessary and meaningful. Magnesium (Mg) alloys possess superb biocompatibility, mechanical property and biodegradability in orthopedic applications. However, whether they possess antitumor property had seldom been reported. In recent years, it showed that zinc (Zn) not only promote the osteogenic activity but also exhibit good antitumor property. In our present study, Zn was selected as an alloying element for the Mg-1Ca-0.5Sr alloy to develop a multifunctional material with antitumor property. We investigated the influence of the Mg-1Ca-0.5Sr-xZn (x = 0, 2, 4, 6 wt%) alloys extracts on the proliferation rate, cell apoptosis, migration and invasion of the U2OS cell line. Our results show that Zn containing Mg alloys extracts inhibit the cell proliferation by alteration the cell cycle and inducing cell apoptosis via the activation of the mitochondria pathway. The cell migration and invasion property were also suppressed by the activation of MAPK (mitogen-activated protein kinase) pathway. Our work suggests that the Mg-1Ca-0.5Sr-6Zn alloy is expected to be a promising orthopedic implant in osteosarcoma limb-salvage surgery for avoiding tumor recurrence and metastasis