Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Med ; 30(3): 896-904, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38365949

ABSTRACT

New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.ClinicalTrials.gov identifier: NCT03557281 .


Subject(s)
Amino Acyl-tRNA Synthetases , Tuberculosis, Pulmonary , Tuberculosis , Male , Humans , Rifampin/therapeutic use , Antitubercular Agents/adverse effects , Tuberculosis/drug therapy , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/microbiology , Amino Acyl-tRNA Synthetases/therapeutic use
2.
PLoS Negl Trop Dis ; 17(11): e0011795, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38011278

ABSTRACT

Burkholderia pseudomallei is the causative agent of melioidosis, which is increasingly being reported worldwide. Mortality rates as high as 40% have been reported based on clinical patient outcomes in the endemic areas of Australia and Thailand. Novel therapies are needed to reduce treatment duration and adverse effects and improve treatment outcomes. Epetraborole, a novel antibiotic, targets leucyl-tRNA synthetase (LeuRS), an essential enzyme that catalyzes the attachment of leucine to transfer RNA. Epetraborole was evaluated for in vitro activity and efficacy in a murine model to assess clinical relevance against Burkholderia pseudomallei infections for possible treatment of melioidosis. Epetraborole was tested against 13 clinically derived and three reference B. pseudomallei strains that have a broad spectrum of susceptibilities to the standard-of-care (SoC) drugs for melioidosis, which showed that epetraborole exhibited minimal inhibitory concentrations of 0.25-4 µg/mL. Ex vivo studies using THP-1 macrophages confirmed the potency of epetraborole and demonstrated synergy between epetraborole and ceftazidime. In the acute pulmonary murine infection model of melioidosis, epetraborole demonstrated equivalent efficacy when delivered orally or subcutaneously, which compared well with the standard-of-care drug ceftazidime. In addition, adding epetraborole to ceftazidime significantly improved antimicrobial activity in this animal model. This work warrants further exploration of epetraborole as a candidate for treating melioidosis and substantiates LeuRS as a clinically relevant drug target in B. pseudomallei.


Subject(s)
Amino Acyl-tRNA Synthetases , Burkholderia pseudomallei , Melioidosis , Animals , Mice , Humans , Ceftazidime/pharmacology , Ceftazidime/therapeutic use , Melioidosis/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Amino Acyl-tRNA Synthetases/pharmacology , Amino Acyl-tRNA Synthetases/therapeutic use
3.
Kurume Med J ; 69(1.2): 19-30, 2023 Nov 30.
Article in English | MEDLINE | ID: mdl-37544752

ABSTRACT

OBJECTIVE: Anti-aminoacyl-tRNA synthetase antibody-positive polymyositis/dermatomyositis-associ ated interstitial lung disease (ARS-ILD) has a good prognosis, with few cases progressing to respiratory failure. This study aimed to determine factors predictive of lung function changes in patients with ARS-ILD. METHODS: We retrospectively studied 49 patients with ARS-ILD treated at Kurume University Hospital Hospital between 2000 and 2018. We followed 30 patients for more than 2 years after prednisolone (PSL) therapy, with or without calcineurin inhibitors (CNIs), evaluating clinical, physiological, computed tomography, pulmonary func tion, and serological data. RESULTS: After treatment for 24 months, no significant differences were noted between clinical parameters and improvement in forced vital capacity (FVC), %FVC, % carbon monoxide diffusing capacity/alveolar volume (%DLCO), and %DLCO/alveolar volume. Conversely, the annual change of %FVC significantly correlated with the Medical Research Council dyspnea scale grade and %FVC at the first visit and treatment. Furthermore, the annual change of %DLCO/VA significantly correlated with the duration from the first visit to treatment initiation. CONCLUSION: Compared with PSL monotherapy, combining PSL and CNI showed greater mitigation of %FVC decline. The time from onset of ARS-ILD to the first visit is critical for preventing a decline in lung function, and as such, patients should be monitored carefully.


Subject(s)
Amino Acyl-tRNA Synthetases , Dermatomyositis , Lung Diseases, Interstitial , Humans , Dermatomyositis/drug therapy , Calcineurin Inhibitors/therapeutic use , Amino Acyl-tRNA Synthetases/therapeutic use , Retrospective Studies , Prednisolone/therapeutic use , Autoantibodies/therapeutic use , Lung Diseases, Interstitial/drug therapy , Lung
4.
Future Med Chem ; 14(17): 1223-1237, 2022 09.
Article in English | MEDLINE | ID: mdl-35876255

ABSTRACT

Background: The most serious challenge in the treatment of tuberculosis is the multidrug resistance of Mycobacterium tuberculosis to existing antibiotics. As a strategy to overcome resistance we used a multitarget drug design approach. The purpose of the work was to discover dual-targeted inhibitors of mycobacterial LeuRS and MetRS with machine learning. Methods: The artificial neural networks were built using module nnet from R 3.6.1. The inhibitory activity of compounds toward LeuRS and MetRS was investigated in aminoacylation assays. Results: Using a machine-learning approach, we identified dual-targeted inhibitors of LeuRS and MetRS among 2-(quinolin-2-ylsulfanyl)-acetamide derivatives. The most active compound inhibits MetRS and LeuRS with IC50 values of 33 µm and 23.9 µm, respectively. Conclusion: 2-(Quinolin-2-ylsulfanyl)-acetamide scaffold can be useful for further research.


Subject(s)
Amino Acyl-tRNA Synthetases , Mycobacterium tuberculosis , Tuberculosis , Acetamides/therapeutic use , Amino Acyl-tRNA Synthetases/therapeutic use , Humans , Machine Learning , Tuberculosis/drug therapy , Tuberculosis/microbiology
5.
EMBO Mol Med ; 5(3): 332-43, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23427196

ABSTRACT

Aminoacyl-tRNA synthetases (ARSs) are essential and ubiquitous 'house-keeping' enzymes responsible for charging amino acids to their cognate tRNAs and providing the substrates for global protein synthesis. Recent studies have revealed a role of multiple ARSs in pathology, and their potential use as pharmacological targets and therapeutic reagents. The ongoing discovery of genetic mutations in human ARSs is increasing exponentially and can be considered an important determinant of disease etiology. Several chemical compounds target bacterial, fungal and human ARSs as antibiotics or disease-targeting medicines. Remarkably, ongoing exploration of noncanonical functions of ARSs has shown important contributions to control of angiogenesis, inflammation, tumourigenesis and other important physiopathological processes. Here, we summarize the roles of ARSs in human diseases and medicine, focusing on the most recent and exciting discoveries.


Subject(s)
Amino Acyl-tRNA Synthetases/metabolism , Protein Biosynthesis , Amino Acyl-tRNA Synthetases/antagonists & inhibitors , Amino Acyl-tRNA Synthetases/genetics , Amino Acyl-tRNA Synthetases/therapeutic use , Aminoacylation , Animals , Anti-Bacterial Agents/therapeutic use , Antifungal Agents/therapeutic use , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Charcot-Marie-Tooth Disease/drug therapy , Charcot-Marie-Tooth Disease/enzymology , Charcot-Marie-Tooth Disease/genetics , Enzyme Replacement Therapy , Fungal Proteins/antagonists & inhibitors , Fungal Proteins/metabolism , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Mitochondrial Diseases/drug therapy , Mitochondrial Diseases/enzymology , Mitochondrial Diseases/genetics , Mutation , Phenotype , Protein Biosynthesis/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL
...