clindamycin-phosphate 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

Infections that occur after intraabdominal surgery still cause considerable morbidity and mortality despite the administration of prophylactic antibiotics. Increasing the number of neutrophils may also be a prophylactic approach, and granulocyte colony-stimulating factor (G-CSF) has been found to be beneficial in different animal models of peritonitis and sepsis. It is the combination of G-CSF and antibiotics, however, that is clinically relevant. Treatment of mice with G-CSF that was started before cecal ligation and puncture and continued afterward with antibiotics improved survival, decreased splenic bacterial colony-forming units and serum tumor necrosis factor, and increased serum interleukin-10, compared with treatment with antibiotics alone or with saline. Compared with saline, antibiotics alone increased tumor necrosis factor and did not affect interleukin-10. Thus, G-CSF confers onto antibiotics beneficial antiinfectious and antiinflammatory properties. A prophylactic regimen combining G-CSF and antibiotics may help prevent severe infectious complications following intraabdominal surgery.

Topics: Animals; Anti-Bacterial Agents; Antibiotic Prophylaxis; Cecum; Clindamycin; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Gentamicins; Granulocyte Colony-Stimulating Factor; Interleukin-10; Interleukin-6; Leukocyte Count; Mice; Neutrophils; Peritonitis; Sepsis; Survivors; Tumor Necrosis Factor-alpha

Topics: Analysis of Variance; Animals; Cefazolin; Clindamycin; Disease Models, Animal; Dogs; Drug Therapy, Combination; Escherichia coli Infections; Gentamicins; Graft Rejection; Immunosuppressive Agents; Lung Transplantation; Male; Neutrophils; Pneumonia, Bacterial; Postoperative Complications; Pulmonary Alveoli; Transplantation, Homologous

The efficacy of pharmacologic doses of steroids in the treatment of septic shock was evaluated using a laboratory model. The model produced a septic insult of gradual onset followed by a rapid progression, allowing for the evaluation of postcontamination therapeutic regimens. In Sprague-Dawley rats, the cecum was ligated distal to the ileocecal valve and doubly punctured. Control animals (n = 41) received no postoperative therapy. Mortality was 37 per cent at 24 hours and 90 per cent at 48 hours. Approximately 25 animals were assigned to each of five experimental groups. Pharmacologic doses of methylprednisolone at four and eight hours postoperatively did not alter survival. Short-term gentamicin (STG) at four and eight hours improved early survival, which then declined to control values. Addition of steroid to STG had no effect. Long-term gentamicin (LTG) administered through the third postoperative day produced significant increased survival over controls throughout the study. Pharmacologic doses of steroid at four and eight hours added to LTG resulted in a significant increase (P less than 0.05) in survival rate over the treatment with LTG alone.

Topics: Animals; Cecum; Clindamycin; Disease Models, Animal; Female; Gentamicins; Glucocorticoids; Male; Methylprednisolone Hemisuccinate; Rats; Rats, Inbred Strains; Shock, Septic; Time Factors