Computational Mutagenesis and Inhibition of Staphylococcus aureus AgrA LytTR Domain Using Phenazine Scaffolds: Insight From a Biophysical Study.
Biofilm formation by Staphylococcus aureus is a major challenge in clinical settings due to its role in persistent infections. The AgrA protein, a key regulator in biofilm development, is a promising target for therapeutic intervention. This study investigates the antibiofilm potential of halogenate...
| Published in: | BioMed Research International Vol. 2024; pp. 1 - 16 |
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| Main Authors: | , , , , |
| Format: | equations & formulas pictorial research tables/charts Journal Article |
| Published: |
Wiley-Blackwell
9/17/2024
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=179685084&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 179685084 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 23146133 FT2T jtl: BioMed Research International issn: 23146133 maglogo: N pubinfo: dt: 9/17/2024 vid: 2024 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 179685084 179685084 179685084 10.1155/2024/8843954 179685084 ppf: 1 ppct: 15 formats: fmt: – @attributes: type: T – @attributes: type: C – @attributes: type: P tig: atl: Computational Mutagenesis and Inhibition of Staphylococcus aureus AgrA LytTR Domain Using Phenazine Scaffolds: Insight From a Biophysical Study. aug: au: Manu, Prince Nketia, Prisca Baah Osei-Poku, Priscilla Kwarteng, Alexander Cantore, Stefania affil: Department of Chemistry,, Kwame Nkrumah University of Science and Technology,, Kumasi, Ghana, knust.edu.gh sug: subj: Staphylococcal Infections Drug Therapy Staphylococcus Aureus Antibiotics Therapeutic Use Heterocyclic Compounds Therapeutic Use Heterocyclic Compounds Pharmacodynamics Bacterial Proteins Drug Effects Biofilms Drug Effects Mutation Molecular Docking Simulation Drug Development In Vitro Studies Biophysiological Methods Bacterial Physiology Descriptive Statistics Virulence Drug Resistance, Microbial Binding Sites Bacterial Infections ab: Biofilm formation by Staphylococcus aureus is a major challenge in clinical settings due to its role in persistent infections. The AgrA protein, a key regulator in biofilm development, is a promising target for therapeutic intervention. This study investigates the antibiofilm potential of halogenated phenazine compounds by targeting AgrA and explores their molecular interactions to provide insights for drug development. We employed molecular docking, molecular dynamics simulations, and computational mutagenesis to evaluate the binding of halogenated phenazine compounds (C1 to C7, HP, and HP‐14) to AgrA. Binding free energy analysis was performed to assess the affinity of these compounds for the AgrA‐DNA complex. Additionally, the impact of these compounds on AgrA's structural conformation and salt bridge interactions was examined. The binding‐free energy analysis revealed that all compounds enhance binding affinity compared to the Apo form of AgrA, which has a ΔGbind of −80.75 kcal/mol. The strongest binding affinities were observed with compounds C7 (−113.84 kcal/mol), HP‐14 (−115.23 kcal/mol), and HP (−112.28 kcal/mol), highlighting their effectiveness. Molecular dynamics simulations demonstrated that these compounds bind at the hydrophobic cleft of AgrA, disrupting essential salt bridge interactions between His174‐Glu163 and His174‐Glu226. This disruption led to structural conformational changes and reduced DNA binding affinity, aligning with experimental findings on biofilm inhibition. The halogenated phenazine compounds effectively inhibit biofilm formation by targeting AgrA, disrupting its DNA‐binding function. The study supports the potential of these compounds as antibiofilm agents and provides a foundation for rational drug design targeting the AgrA‐DNA interaction. Future research should focus on further optimizing these lead compounds and exploring additional active sites on AgrA to develop novel treatments for biofilm‐associated infections. pubtype: Academic Journal doctype: equations & formulas pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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