title: Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK).
abstract: BACKGROUND
  Due to the widespread abusage of antibiotics, antibiotic-resistance in Streptococcus pneumoniae (S. pneumoniae) has been increasing quickly in recent years, and it is obviously urgent to develop new types of antibiotics. Two-component systems (TCSs) are the major signal transduction pathways in bacteria and have emerged as potential targets for antibacterial drugs. Among the 13 pairs of TCSs proteins presenting in S. pneumoniae, VicR/K is the unique one essential for bacterium growth, and block agents to which, if can be found, may be developed as effective antibiotics against S. pneumoniae infection.
  
  
  RESULTS
  Using a structure-based virtual screening (SBVS) method, 105 compounds were computationally identified as potential inhibitors of the histidine kinase (HK) VicK protein from the compound library SPECS. Six of them were then validated in vitro to be active in inhibiting the growth of S. pneumoniae without obvious cytotoxicity to Vero cell. In mouse sepsis models, these compounds are still able to decrease the mortality of the mice infected by S. pneumoniae and one compound even has significant therapeutic effect.
  
  
  CONCLUSIONS
  To our knowledge, these compounds are the first reported inhibitors of HK with antibacterial activity in vitro and in vivo, and are novel lead structures for developing new drugs to combat pneumococcal infection.
authors: Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Faculty of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China. linan101@tom.com
authors: Nan
authors: N
authors: Li
authors: Fei
authors: F
authors: Wang
authors: Siqiang
authors: S
authors: Niu
authors: Ju
authors: J
authors: Cao
authors: Kaifeng
authors: K
authors: Wu
authors: Youqiang
authors: Y
authors: Li
authors: Nanlin
authors: N
authors: Yin
authors: Xuemei
authors: X
authors: Zhang
authors: Weiliang
authors: W
authors: Zhu
authors: Yibing
authors: Y
authors: Yin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D019295:Computational Biology; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D000071677:Histidine Kinase; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D017433:Protein Structure, Secondary; D018805:Sepsis / Q000188:drug therapy; D016415:Sequence Alignment; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D000071677:Histidine Kinase