title: Structure-based discovery of inhibitors of the YycG histidine kinase: new chemical leads to combat Staphylococcus epidermidis infections.
abstract: BACKGROUND
  Coagulase-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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Key laboratory of Medical Molecular Virology, Ministry of Education and Ministry of Public Health, Institute of Medical Microbiology, Shanghai Medical School of Fudan University, Shanghai, PR China. 021101043@fudan.edu.cn
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Qin
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Yang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Soeren
authors.initials: S
authors.lastname: Molin
authors.forename: Antoine
authors.initials: A
authors.lastname: Danchin
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Di
authors.initials: D
authors.lastname: Qu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018441:Biofilms / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006461:Hemolysis / Q000187:drug effects; D000071677:Histidine Kinase; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013203:Staphylococcal Infections / Q000382:microbiology / Q000517:prevention & control; D013212:Staphylococcus epidermidis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D000071677:Histidine Kinase; C515949:YycG protein, Staphylococcus epidermidis