ArticleCombinatorial chemistry & high throughput screening2016
A High-Throughput Assay for Developing Inhibitors of PhoP, a Virulence Factor of Mycobacterium tuberculosis.
Article in Combinatorial chemistry & high throughput screening, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 11 citations in OpenAlex.
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- Targeting of Regulators as a Promising Approach in the Search for Novel Antimicrobial Agents.Microorganisms · 2022Article
- Whole-Genome sequencing and comparative genomics of Mycobacterium spp. from farmed Atlantic and coho salmon in Chile.Antonie van Leeuwenhoek · 2021Article
- Deciphering Molecular Virulence Mechanism of Mycobacterium tuberculosis Dop isopeptidase Based on Its Sequence-Structure-Function Linkage.The protein journal · 2020Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
backgroundTuberculosis (TB) kills over 1.5 million people per year despite the available anti-TB drugs. The long duration needed to treat TB by the current TB drugs, which target the essential cellular activities, inevitably leads to the emergence of drug-resistance. The emergence of drug-resistant TB prompts for an urgent need for new and more effective drugs.
objectiveThe response regulator PhoP, an essential virulence factor of Mycobacterium tuberculosis (MTB), is an attractive target for developing novel anti- TB drugs. This study aims to develop a robust high-throughput screening assay to identify PhoP inhibitors that disrupt the PhoP-DNA binding.
methodGuided by the crystal structure of the PhoP-DNA complex, we designed and developed an assay based on Foster resonance energy transfer (FRET) by labeling Cy3 on the DNA and Cy5 on PhoP. We screened compound libraries for inhibitors that dissociated the PhoP-DNA complex by detection of the FRET signal. Hits were confirmed for their direct binding to PhoP by thermal shift assays.
resultsFrom a test screening of ~6,000 bioactive compounds and approved drugs, three active compounds were identified that directly bound to PhoP and inhibited the PhoP-DNA interactions. These three PhoP inhibitors can be further developed to improve potency and are useful to study the mechanism of inhibition.
conclusionOur results demonstrated that this FRET-based PhoP-DNA binding assay is valid for additional compound library screening to identify new leads for developing novel TB drugs that target the virulence of MTB.
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