RESUMO
The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.
Assuntos
Antituberculosos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Administração Oral , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Antituberculosos/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Leucina-tRNA Ligase/química , Leucina-tRNA Ligase/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/genética , Mycobacterium tuberculosis/genética , Inibidores da Síntese de Proteínas/administração & dosagem , Inibidores da Síntese de Proteínas/química , Inibidores da Síntese de Proteínas/farmacocinética , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Células VeroRESUMO
BACKGROUND: Empathy is at the core of patient-centred care. Evidence has continually found that empathy helps foster therapeutic relationships and is essential in the delivery of quality healthcare. In India, many factors are barriers to empathy for nursing professionals. OBJECTIVES: DESIGN AND METHODS: The IDEO design thinking process was followed to design the game. A focus group discussion with 18 nurses helped identify relevant scenarios and barriers to empathy. A scenario of an interaction between a nurse and a cancer patient was identified to create the game. The game mechanics, rubrics, and scenarios were built based on feedback from diverse professionals consisting of doctors, nurses, and UX designers. A learner feedback form assessing usability, contextual specificity, engagement, and perceived learnability was created and its reliability was tested. The game was tested on 60 nurses, followed by administration of the learner feedback form. To assess changes in empathy, an empathy scale was administered before the intervention and seven days after the intervention on 20 nurses. RESULTS: The learner feedback form was found to have Cronbach's Alpha >0.70, and therefore reliable. The responses to the learner feedback form were analysed using the Chi Square test and were found to be positive and statistically significant (p-value<0.001). The differences in pretest and posttest empathy scores were analysed using the Wilcoxon Signed Ranks test and were found to be statistically significant as well (p-value<0.001). CONCLUSIONS: The positive response to the learner feedback form, and the improvement in empathy scores after the intervention, indicates that games have a potential role in teaching empathy to Nursing Professionals.
RESUMO
Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.
Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Antibacterianos/farmacologia , Compostos de Boro/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Aminoacil-tRNA Sintetases/metabolismo , Animais , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Compostos de Boro/síntese química , Compostos de Boro/farmacocinética , Cristalografia por Raios X , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/enzimologia , Feminino , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Leucina/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pseudomonas aeruginosa/enzimologia , Relação Estrutura-Atividade , Coxa da Perna/microbiologia , Inibidores de beta-Lactamases , beta-Lactamases/metabolismoRESUMO
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacocinética , Animais , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Pirimidinonas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Transplante Heterólogo , Regulação para CimaRESUMO
A new class of benzoxaborole ß-lactamase inhibitors were designed and synthesized. 6-Aryloxy benzoxaborole 22 inhibited AmpC P99 and CMY-2 with K(i) values in the low nanomolar range. Compound 22 restored antibacterial activity of ceftazidime against Enterobacter cloacae P99 expressing AmpC, a class C ß-lactamase enzyme. The SAR around the arylbenzoxaboroles, which included the influence of linker and substitutions was also established.
Assuntos
Antibacterianos/síntese química , Benzoxazóis/química , Compostos de Boro/química , Inibidores Enzimáticos/síntese química , Pirazinas/síntese química , Inibidores de beta-Lactamases , Antibacterianos/química , Antibacterianos/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Enterobacter cloacae/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Testes de Sensibilidade Microbiana , Pirazinas/química , Pirazinas/farmacologia , Relação Estrutura-Atividade , beta-Lactamases/metabolismoRESUMO
There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656). This molecule shows potent inhibition of Mtb LeuRS (IC50 = 0.20 µM) and in vitro antitubercular activity (Mtb H37Rv MIC = 0.08 µM). Additionally, it is highly selective for the Mtb LeuRS enzyme with IC50 of >300 µM and 132 µM for human mitochondrial LeuRS and human cytoplasmic LeuRS, respectively. In addition, it exhibits remarkable PK profiles and efficacy against Mtb in mouse TB infection models with superior tolerability over initial leads. This compound has been progressed to clinical development for the treatment of tuberculosis.