ethionamide and Disease-Models--Animal

A new class of antibacterials, diarylquinolines, was identified. The lead compound, R207910 (TMC207), was able to inhibit Mycobacterium tuberculosis in vitro, in mice and in patients. R207910 targets the mycobacterial ATP synthase. In vitro, it displayed potent activities against both drug-sensitive and multidrug-resistant strains of M. tuberculosis. It was also strongly active against dormant bacilli in the Wayne's dormancy culture system, hypoxia and nitric oxide models. In the murine model, when used alone, it was as active as the triple combination of rifampicin+isoniazid+pyrazinamide. When added to the previous combination or substituted for isoniazid or rifampicin, the treatment including the combinations containing R207910 led to culture conversion after 2 months of therapy. When added to the combination used to treat MDR-TB or substituted for moxifloxacin or ethionamide, the combinations containing R207910 led to culture conversion after 2 months of therapy. In MDR-TB infected patients, R207910 combined with second line drugs was able to convert more sputum cultures (47.6%) than the placebo combined to second line drugs regimen (8.7%).

Topics: Animals; Anti-Infective Agents; Antitubercular Agents; Aza Compounds; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Ethionamide; Fluoroquinolones; Humans; Mice; Moxifloxacin; Mycobacterium tuberculosis; Placebos; Quinolines; Tuberculosis

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

Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered "booster" molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, "green" β-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy.

Topics: Administration, Inhalation; Animals; Antitubercular Agents; beta-Cyclodextrins; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Synergism; Drug Therapy, Combination; Ethionamide; Female; Humans; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nanoparticles; Oxadiazoles; Piperidines; Polylactic Acid-Polyglycolic Acid Copolymer; RAW 264.7 Cells; Solubility; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Aniline Compounds; Animals; Dapsone; Disease Models, Animal; Drug Combinations; Ethionamide; Humans; Isoniazid; Leprosy; Mice; Models, Biological; Mycobacterium Infections; Phenazines; Pyrazines; Rabbits; Rifampin; Sulfonamides; Trimethoprim

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Disease Models, Animal; Ethionamide; Female; Fertility; Fetus; Gestational Age; Gonads; Infant Mortality; Kidney; Liver; Long-Term Care; Male; Mice; Pregnancy; Pregnancy, Prolonged; Sex Factors; Tuberculosis

Topics: Animals; Cell Count; Chronic Disease; Disease Models, Animal; Drug Synergism; Ethambutol; Ethionamide; Isoniazid; Lung; Mice; Placebos; Rifampin; Streptomycin; Tuberculosis

Topics: Animals; Antitubercular Agents; Cycloserine; Dapsone; Disease Models, Animal; Drug Synergism; Ethambutol; Ethionamide; Mice; Mycobacterium Infections; Phenylthiourea; Rabbits; Streptomycin; Thioacetazone