retapamulin and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer's disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs-ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin-as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays. We initially screened a database of FDA-approved drugs using molecular docking against the ligand-binding domain of EphA4. Then, we selected 22 candidate drugs and examined their inhibitory activity towards EphA4. Among them, five drugs inhibited EphA4 clustering induced by ephrin-A in cultured primary neurons. Specifically, nilotinib, a kinase inhibitor, inhibited the binding of EphA4 and ephrin-A at micromolar scale in a dosage-dependent manner. Furthermore, nilotinib inhibited the activation of EphA4 and EphA4-dependent growth cone collapse in cultured hippocampal neurons, demonstrating that the drug exhibits EphA4 inhibitory activity in cellular context. As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD.

Topics: Alzheimer Disease; Androstenes; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cyproheptadine; Disease Models, Animal; Diterpenes; Drug Evaluation, Preclinical; Hippocampus; Ligands; Mice; Mice, Transgenic; Molecular Docking Simulation; Neurons; Protein Binding; Protein Domains; Pyrimidines; Receptor, EphA4

To assess different concentrations and formulations of topical ozenoxacin using a mouse model of Staphylococcus aureus dermal infection for identification of the best formulation for treating patients with impetigo.. The efficacy of ozenoxacin formulations was compared with vehicle control, mupirocin and retapamulin ointments in a mouse model.. The most effective concentrations of ozenoxacin for reducing S. aureus counts after dermal application were 1 and 2%. Direct comparison of two batches of 1% ozenoxacin ointment and cream with 1% retapamulin and 2% mupirocin ointments in the mouse model showed superior efficacy of ozenoxacin.. 1% ozenoxacin ointment and cream were the most effective formulations in significantly reducing bacterial load in S. aureus dermally infected mice.

Topics: Administration, Topical; Aminopyridines; Animals; Animals, Outbred Strains; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Humans; Impetigo; Mice; Mupirocin; Ointments; Quinolones; Skin Cream; Staphylococcus aureus; Treatment Outcome; Wound Infection

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) frequently causes skin and soft tissue infections, including impetigo, cellulitis, folliculitis, and infected wounds and ulcers. Uncomplicated CA-MRSA skin infections are typically managed in an outpatient setting with oral and topical antibiotics and/or incision and drainage, whereas complicated skin infections often require hospitalization, intravenous antibiotics, and sometimes surgery. The aim of this study was to develop a mouse model of CA-MRSA wound infection to compare the efficacy of commonly used systemic and topical antibiotics. A bioluminescent USA300 CA-MRSA strain was inoculated into full-thickness scalpel wounds on the backs of mice and digital photography/image analysis and in vivo bioluminescence imaging were used to measure wound healing and the bacterial burden. Subcutaneous vancomycin, daptomycin, and linezolid similarly reduced the lesion sizes and bacterial burden. Oral linezolid, clindamycin, and doxycycline all decreased the lesion sizes and bacterial burden. Oral trimethoprim-sulfamethoxazole decreased the bacterial burden but did not decrease the lesion size. Topical mupirocin and retapamulin ointments both reduced the bacterial burden. However, the petrolatum vehicle ointment for retapamulin, but not the polyethylene glycol vehicle ointment for mupirocin, promoted wound healing and initially increased the bacterial burden. Finally, in type 2 diabetic mice, subcutaneous linezolid and daptomycin had the most rapid therapeutic effect compared with vancomycin. Taken together, this mouse model of CA-MRSA wound infection, which utilizes in vivo bioluminescence imaging to monitor the bacterial burden, represents an alternative method to evaluate the preclinical in vivo efficacy of systemic and topical antimicrobial agents.

Topics: Acetamides; Administration, Oral; Administration, Topical; Animals; Anti-Bacterial Agents; Bacterial Load; Bridged Bicyclo Compounds, Heterocyclic; Clindamycin; Community-Acquired Infections; Daptomycin; Diabetes Mellitus, Type 2; Disease Models, Animal; Diterpenes; Doxycycline; Linezolid; Luminescent Measurements; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Mupirocin; Oxazolidinones; Skin; Soft Tissue Infections; Staphylococcal Infections; Staphylococcal Skin Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin; Wound Healing

Staphylococcus aureus skin infections represent a significant public health threat because of the emergence of antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA). As greater understanding of protective immune responses and more effective antimicrobial therapies are needed, a S. aureus skin wound infection model was developed in which full-thickness scalpel cuts on the backs of mice were infected with a bioluminescent S. aureus (methicillin sensitive) or USA300 community-acquired MRSA strain and in vivo imaging was used to noninvasively monitor the bacterial burden. In addition, the infection-induced inflammatory response was quantified using in vivo fluorescence imaging of LysEGFP mice. Using this model, we found that both IL-1α and IL-1β contributed to host defense during a wound infection, whereas IL-1β was more critical during an intradermal S. aureus infection. Furthermore, treatment of a USA300 MRSA skin infection with retapamulin ointment resulted in up to 85-fold reduction in bacterial burden and a 53% decrease in infection-induced inflammation. In contrast, mupirocin ointment had minimal clinical activity against this USA300 strain, resulting in only a 2-fold reduction in bacterial burden. Taken together, this S. aureus wound infection model provides a valuable preclinical screening method to investigate cutaneous immune responses and the efficacy of topical antimicrobial therapies.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Community-Acquired Infections; Dermatitis; Dermoscopy; Disease Models, Animal; Diterpenes; Drug Monitoring; Green Fluorescent Proteins; Interleukin-1alpha; Interleukin-1beta; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Mupirocin; Staphylococcal Skin Infections