A novel methionyl-tRNA synthetase inhibitor targeting gram-positive bacterial pathogens.

New antibiotics are needed to treat gram-positive bacterial pathogens. is a novel inhibitor of methionyl-tRNA synthetase with selective activity against gram-positive bacteria. The minimum inhibitory concentrations (MICs) against and species range from 0.

Case Report: Miltefosine Failure and Spontaneous Resolution of Cutaneous Leishmaniasis braziliensis.

Cutaneous leishmaniasis (CL) is often caused by Leishmania braziliensis (L. braziliensis) in South America. Because of the risk for mucocutaneous leishmaniasis, L.

Spontaneous Selection of Drug Resistance in a Calf Model of Infection.

The intestinal protozoan is a leading cause of diarrheal disease and mortality in young children. There is currently no fully effective treatment for cryptosporidiosis, which has stimulated interest in anticryptosporidial development over the last ∼10 years, with numerous lead compounds identified, including several tRNA synthetase inhibitors. Here, we report the results of a dairy calf efficacy trial of the methionyl-tRNA ( MetRS [MetRS]) synthetase inhibitor 2093 and the spontaneous emergence of drug resistance.

Synthesis and Structure-Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases.

Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which invariably leads to fatal cases. Hence, there is an urgent need for new antitrypanosomal drugs.

Clinical Features and Outcomes of 105 Hospitalized Patients With COVID-19 in Seattle, Washington.

Background: Washington State served as the initial epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in the United States. An understanding of the risk factors and clinical outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) may provide guidance for management.

Methods: All laboratory-confirmed COVID-19 cases in adults admitted to an academic medical center in Seattle, Washington, between 2 March and 26 March 2020 were included.

Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach.

The work began with the screening of a library of 700,000 small molecules for inhibitors of growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 chemically distinct scaffolds for further investigation. The first triage step was the assessment for brain permeability (looking for brain levels at least 20% of plasma levels) in order to optimize the chances of developing candidates for treating late-stage human African trypanosomiasis.

A new chemotype with promise against Trypanosoma cruzi.

Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ≥10. The initial structure-activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi.

Bioactivity of Farnesyltransferase Inhibitors Against and .

The protozoan parasite can induce amebic colitis and amebic liver abscess. First-line drugs for the treatment of amebiasis are nitroimidazoles, particularly metronidazole. Metronidazole has side effects and potential drug resistance is a concern.

Optimization of Methionyl tRNA-Synthetase Inhibitors for Treatment of Infection.

Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV-infected persons. We describe here the discovery and early optimization of a class of imidazopyridine-containing compounds with potential for treating infections.

Triazolopyrimidines and Imidazopyridines: Structure-Activity Relationships and in Vivo Efficacy for Trypanosomiasis.

Better therapeutics are greatly needed to treat patients infected with trypanosomatid parasites such as or . This report describes 28 new imidazopyridines and triazolopyrimidines with potent and selective antitrypanosomal activity. Drug-like properties were demonstrated in a number of in vitro assays.

Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections.

Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm.

1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti- Agents: SAR and in Vivo Efficacy.

A high throughput screening and subsequent hit validation identified compound as an inhibitor of parasite growth. Extensive structure-activity relationship optimization based on antiparasitic activity led to the highly potent compounds, 1-(4-fluorobenzyl)-3-(4-dimethylamino-3-chlorophenyl)-2-thiohydantoin () and 1-(2-chloro-4-fluorobenzyl)-3-(4-dimethylamino-3-methoxyphenyl)-2-thiohydantoin (), with a EC of 3 and 2 nM, respectively. This represents >100-fold improvement in potency compared to compound .