ArticleBMC microbiology2006
Structure-based discovery of inhibitors of the YycG histidine kinase: new chemical leads to combat Staphylococcus epidermidis infections.
Article in BMC microbiology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 108 citations in OpenAlex.
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- Recent Advances in Histidine Kinase-Targeted Antimicrobial Agents.Frontiers in chemistry · 2022Review
- The W-Acidic Motif of Histidine Kinase WalK Is Required for Signaling and Transcriptional Regulation inFrontiers in microbiology · 2022Article
- Antibacterial and anti-biofilm activities of histidine kinase YycG inhibitors against Streptococcus agalactiae.The Journal of antibiotics · 2021Article
- Evaluation of small molecule kinase inhibitors as novel antimicrobial and antibiofilm agents.Chemical biology & drug design · 2021Review
- Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery.Molecules (Basel, Switzerland) · 2021Review
- Targeting a highly conserved domain in bacterial histidine kinases to generate inhibitors with broad spectrum activity.Current opinion in microbiology · 2021Review
- Article
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Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCoagulase-negative Staphylococcus epidermidis has become a major frequent cause of infections in relation to the use of implanted medical devices. The pathogenicity of S. epidermidis has been attributed to its capacity to form biofilms on surfaces of medical devices, which greatly increases its resistance to many conventional antibiotics and often results in chronic infection. It has an urgent need to design novel antibiotics against staphylococci infections, especially those can kill cells embedded in biofilm.
resultsIn this report, a series of novel inhibitors of the histidine kinase (HK) YycG protein of S. epidermidis were discovered first using structure-based virtual screening (SBVS) from a small molecular lead-compound library, followed by experimental validation. Of the 76 candidates derived by SBVS targeting of the homolog model of the YycG HATPase_c domain of S. epidermidis, seven compounds displayed significant activity in inhibiting S. epidermidis growth. Furthermore, five of them displayed bactericidal effects on both planktonic and biofilm cells of S. epidermidis. Except for one, the compounds were found to bind to the YycG protein and to inhibit its auto-phosphorylation in vitro, indicating that they are potential inhibitors of the YycG/YycF two-component system (TCS), which is essential in S. epidermidis. Importantly, all these compounds did not affect the stability of mammalian cells nor hemolytic activities at the concentrations used in our study.
conclusionThese novel inhibitors of YycG histidine kinase thus are of potential value as leads for developing new antibiotics against infecting staphylococci. The structure-based virtual screening (SBVS) technology can be widely used in screening potential inhibitors of other bacterial TCSs, since it is more rapid and efficacious than traditional screening technology.
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