Whole-cell screening for Mycobacterium tuberculosis (Mtb) inhibitors is complicated by the pathogen's slow growth and biocontainment requirements. Here we present a synthetic biology framework for assaying Mtb drug targets in engineered E. coli. We construct Target Essential Surrogate E. coli (TESEC) in which an essential metabolic enzyme is deleted and replaced with an Mtb-derived functional analog, linking bacterial growth to the activity of the target enzyme. High throughput screening of a TESEC model for Mtb alanine racemase (Alr) revealed benazepril as a targeted inhibitor, a result validated in whole-cell Mtb. In vitro biochemical assays indicated a noncompetitive mechanism unlike that of clinical Alr inhibitors. We establish the scalability of TESEC for drug discovery by characterizing TESEC strains for four additional targets.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9262897 | PMC |
| http://dx.doi.org/10.1038/s41467-022-31570-3 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of noncovalent diaminopyrimidine-based Inhibitors for glioblastoma via a dual FAK/DNA targeting strategy.
Eur J Med Chem
January 2025
School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address:
Temozolomide, a widely used alkylating agent for glioblastoma treatment, faces significant challenges due to the development of resistance, which severely impacts patient survival. This underscores the urgent need for novel strategies to overcome this barrier. Focal adhesion kinase (FAK), an intracellular non-receptor tyrosine kinase, is highly expressed in glioblastoma cells and has been identified as a promising therapeutic target for anti-glioblastoma drug development.
View Article and Find Full Text PDFAnxiolytic-like Effect of Chrysin on Female Zebrafish is Likely Mediated by α5 subunits of GABAA Receptors.
Chem Biodivers
January 2025
UNIFESSPA: Universidade Federal do Sul e Sudeste do Para, Faculdade de Psicologia, Rod. BR-230 (Transamazônica), Loteamento Cidade Jardim, Av. dos Ipês, s/n.º - Ci, 68503000, Marabá, BRAZIL.
Chrysin (5,7-dihydroxyflavone) is a natural flavonoid with potential anxiolytic-like effects in preclinical models. Acute treatment with this molecule (0 - 10 mg/kg) produced a biphasic dose-response in the zebrafish light/dark test (LDT), with anxiolytic-like effect at low doses and anxiogenic-like effects at high doses. Chrysin (1 mg/kg) decreased anxiety-like behavior in the zebrafish novel tank test (NTT), but did not prevent the anxiogenic effects of acute stress.
View Article and Find Full Text PDFRepurposing the familiar: Future treatment options against chronic kidney disease.
J Pharm Pharmacol
January 2025
Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, 333031, Rajasthan, India.
Objectives: Chronic kidney disease (CKD) is a serious health issue with rising morbidity and mortality rates. Despite advances in understanding its pathophysiology, effective therapeutic options are limited, necessitating innovative treatment approaches. Also, current frontline treatments that are available against CKD are not uniformly effective and often come with significant side effects.
View Article and Find Full Text PDFProteomic characterization and comparison of the infective and adult life stage secretomes from Necator americanus and Ancylostoma ceylanicum.
PLoS Negl Trop Dis
January 2025
Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
More than 470 million people globally are infected with the hookworms Ancylostoma ceylanicum and Necator americanus, resulting in an annual loss of 2.1 to 4 million disability-adjusted-life-years. Current infection management approaches are limited by modest drug efficacy, the costs associated with frequent mass drug administration campaigns, and the risk of reinfection and burgeoning drug resistance.
View Article and Find Full Text PDFPEGylation of Dipeptide Linker Improves Therapeutic Index and Pharmacokinetics of Antibody-Drug Conjugates.
Bioconjug Chem
January 2025
Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Hydrophobic payloads incorporated into antibody-drug conjugates (ADCs) typically are superior to hydrophilic ones in tumor penetration and "bystander killing" upon release from ADCs. However, they are prone to aggregation and accelerated plasma clearance, which lead to reduced efficacies and increased toxicities of ADC molecules. Shielding the hydrophobicity of payloads by incorporating polyethylene glycol (PEG) elements or sugar groups into the ADC linkers has emerged as a viable alternative to directly adopting hydrophilic payloads.
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!