Tuberculosis poses a major global health problem and multi-drug resistant strains are increasingly prevalent. Hence there is an urgent need to discover new TB drugs. Cell based phenotypic screening represents a powerful approach to identify anti-mycobacterial compounds and elucidate novel targets. Three high throughput phenotypic screens were performed at NITD against mycobacterium. Hits were identified and chemical series selected for optimisation. This produced compounds with good in vitro anti-mycobacterial activity and pharmacokinetic properties. Some compounds displayed oral activity in mouse efficacy models of TB. Herein, we review the TB discovery efforts at NITD and share experiences in optimisation of phenotypic hits, describing challenges encountered and lessons learned. We also offer perspectives to facilitate future selection and advancement of phenotypic hits.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmc.2014.12.031 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Echocardiographic phenotypes of diabetic myocardial disorder: evolution over 15 months follow-up in the ARISE-HF trial.
Cardiovasc Diabetol
January 2025
Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Background: Diabetic myocardial disorder (DbMD, evidenced by abnormal echocardiography or cardiac biomarkers) is a form of stage B heart failure (SBHF) at high risk for progression to overt HF. SBHF is defined by abnormal LV morphology and function and/or abnormal cardiac biomarker concentrations.
Objective: To compare the evolution of four DbMD groups based on biomarkers alone, systolic and diastolic dysfunction alone, or their combination.
Aura phenomenon: a proposal for an etiology-based clinical classification.
J Headache Pain
January 2025
Department of Neuroscience, Bufalini Hospital, AUSL Romagna, Cesena, Italy.
Background: The term "aura" refers to a well-defined pattern of usually positive, progressive, and reversible neurological symptoms, with spreading depolarization as the underlying mechanism. While commonly associated with migraine, aura can also occur in other neurological disorders (i.e.
View Article and Find Full Text PDFThe genetics of non-syndromic dentinogenesis imperfecta: a systematic review.
Eur Arch Paediatr Dent
January 2025
Dental School, The University of Western Australia, 17 Monash Avenue, Nedlands, WA, 6009, Australia.
Purpose: This systematic review aims to consolidate existing genetic and clinical data on non-syndromic dentinogenesis imperfecta (DI) to enhance understanding of its etiology.
Methods: Electronic databases were searched for genetic familial linkage studies published in English without time restrictions. Genetic familial linkage studies that reported cases of Shield's classifications: DI-II, DI-III or DD-II were included.
Small Fibre Pathology in Fibromyalgia: A review.
Pain Ther
January 2025
Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, Clinical Sciences Centre, University Hospital Aintree, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool, L9 7AL, UK.
Fibromyalgia syndrome (FMS) presents a complex and challenging disorder in both the diagnosis and treatment, with emerging evidence suggesting a role of small fibre pathology (SFP) in its pathophysiology. The significance of the role of SFP in FMS remains unclear; however, recent evidence suggests degeneration and dysfunction of the peripheral nervous system, particularly small unmyelinated fibres, which may influence pathophysiology and underlying phenotype. Both skin biopsy and corneal confocal microscopy (CCM) have consistently demonstrated that ~ 50% of people with FMS have SFP.
View Article and Find Full Text PDFInhibition of Mitochondrial Succinate Dehydrogenase with Dimethyl Malonate Promotes M2 Macrophage Polarization by Enhancing STAT6 Activation.
Inflammation
January 2025
Department of Respiratory Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, 518110, China.
Macrophages exhibit diverse phenotypes depending on environment status, which contribute to physiological and pathological processes of immunological diseases, including sepsis, asthma, multiple sclerosis and colitis. The alternative activation of macrophages is tightly regulated to avoid excessive activation and damage of tissues and organs. Certain works characterized that succinate dehydrogenase (SDH) altered function of macrophages and promoted inflammatory response in M1 macrophages via mitochondrial reactive oxygen species (ROS).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!