Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK).
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.
Li
Nan
N
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Faculty of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China. linan101@tom.com
Wang
Fei
F
Niu
Siqiang
S
Cao
Ju
J
Wu
Kaifeng
K
Li
Youqiang
Y
Yin
Nanlin
N
Zhang
Xuemei
X
Zhu
Weiliang
W
Yin
Yibing
Y
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
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D000071677:Histidine Kinase