ArticleAntimicrobial agents and chemotherapy2014
Assessment of Mycobacterium tuberculosis pantothenate kinase vulnerability through target knockdown and mechanistically diverse inhibitors.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 27 citations in OpenAlex.
- In Silico Approach: Anti-Tuberculosis Activity of Caespitate in the H37Rv Strain.Current issues in molecular biology · 2024Article
- In silico study of bioactive compounds derived from Indonesian marine invertebrates as a novel antituberculosis agent.Turkish journal of medical sciences · 2024Article
- Polypharmacology-Driven Discovery and Design of Highly Selective, Dual and Multitargeting Inhibitors ofCurrent drug targets · 2024Review
- Probing coenzyme A homeostasis with semisynthetic biosensors.Nature chemical biology · 2023Article
- A d-Phenylalanine-Benzoxazole Derivative Reveals the Role of the Essential Enzyme Rv3603c in the Pantothenate Biosynthetic Pathway ofACS infectious diseases · 2022Article
- TargetingACS infectious diseases · 2021Article
- Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis.Molecules (Basel, Switzerland) · 2020Review
- Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents.Frontiers in cellular and infection microbiology · 2020Review
- Handling the Hurdles on the Way to Anti-tuberculosis Drug Development.Frontiers in chemistry · 2020Review
- Revisiting Drug Development Against the Neglected Tropical Disease, Amebiasis.Frontiers in cellular and infection microbiology · 2020Review
- Characterization and validation of Entamoeba histolytica pantothenate kinase as a novel anti-amebic drug target.International journal for parasitology. Drugs and drug resistance · 2018Article
- A multitarget approach to drug discovery inhibiting Mycobacterium tuberculosis PyrG and PanK.Scientific reports · 2018Article
- Review
- Programmable transcriptional repression in mycobacteria using an orthogonal CRISPR interference platform.Nature microbiology · 2017Article
- Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis.ACS infectious diseases · 2016Article
- Essentiality Assessment of Cysteinyl and Lysyl-tRNA Synthetases of Mycobacterium smegmatis.PloS one · 2016Article
- The application of tetracyclineregulated gene expression systems in the validation of novel drug targets in Mycobacterium tuberculosis.Frontiers in microbiology · 2015Review
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Authors and funding
27 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme A (CoA) biosynthesis. In our earlier reports, we had established that the type I isoform encoded by the coaA gene is an essential pantothenate kinase in Mycobacterium tuberculosis, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of PanK inhibitors. The present report summarizes the synthesis and expansion efforts to understand the structure-activity relationships leading to the optimization of enzyme inhibition along with antimycobacterial activity. Additionally, we report the progression of two distinct classes of inhibitors, the triazoles, which are ATP competitors, and the biaryl acetic acids, with a mixed mode of inhibition. Cocrystallization studies provided evidence of these inhibitors binding to the enzyme. This was further substantiated with the biaryl acids having MIC against the wild-type M. tuberculosis strain and the subsequent establishment of a target link with an upshift in MIC in a strain overexpressing PanK. On the other hand, the ATP competitors had cellular activity only in a M. tuberculosis knockdown strain with reduced PanK expression levels. Additionally, in vitro and in vivo survival kinetic studies performed with a M. tuberculosis PanK (MtPanK) knockdown strain indicated that the target levels have to be significantly reduced to bring in growth inhibition. The dual approaches employed here thus established the poor vulnerability of PanK in M. tuberculosis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.