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Targeting InhA in drug-resistant Mycobacterium tuberculosis: potent antimycobacterial activity of diaryl ether dehydrozingerone derivatives.
Arch Microbiol
January 2025
Clinical Microbiology and PK-PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, J&K, 190005, India.
Tuberculosis (TB) remains a major global threat, with 10 million new cases and 1.5 million deaths each year. In multidrug-resistant tuberculosis (MDR-TB), resistance is most commonly observed against isoniazid (INH) and rifampicin (RIF), the two frontline drugs.
View Article and Find Full Text PDFExpanding the Chemical Space of Reverse Fosmidomycin Analogs.
ACS Med Chem Lett
January 2025
Institute of Pharmaceutical and Medicinal Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for , , and that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin.
View Article and Find Full Text PDFCost-effectiveness of targeted next-generation sequencing (tNGS) for detection of tuberculosis drug resistance in India, South Africa and Georgia: a modeling analysis.
EClinicalMedicine
January 2025
School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.
Background: Targeted next-generation sequencing (tNGS) is promising alternative to phenotypic drug susceptibility testing (pDST) for detecting drug-resistant tuberculosis (DRTB). This study explored the potential cost-effectiveness of tNGS for the diagnosis of DR-TB across 3 settings: India, South Africa and Georgia.
Methods: To inform WHO guideline development group (GDG) on tNGS we developed a stochastic decision analysis model and assessed cost-effectiveness of tNGS for DST among rifampicin resistance individuals.
Significant reduction of seizure frequency in patients with drug-resistant epilepsy by vagus nerve stimulation: Systematic review and meta-analysis.
Epilepsy Res
January 2025
Consultant Neurologist, Dr. Kamakshi Memorial Hospital, Chennai, India.
Background: Epilepsy is a major neurological disorder, typically managed with Anti-Seizure Medication (ASM). Nevertheless, a substantial 30 % of patients did not respond satisfactorily to ASMs, classifying their condition as Drug-Resistant Epilepsy (DRE). Vagus Nerve Stimulation (VNS) was recommended as a potential solution.
View Article and Find Full Text PDF( ) is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi-(MDR) and extensively-(XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes.
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