Research article

Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK)

Nan Li^{* 1} , Fei Wang^{* 2} , Siqiang Niu¹ , Ju Cao¹ , Kaifeng Wu¹ , Youqiang Li¹ , Nanlin Yin¹ , Xuemei Zhang¹ , Weiliang Zhu² and Yibing Yin¹

¹Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Faculty of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China

²Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Material Medical, Graduate School of Chinese Academy of Sciences, Shanghai 201203, PR China

author email corresponding author email* Contributed equally

BMC Microbiology 2009, 9:129doi:10.1186/1471-2180-9-129

Published:	27 June 2009

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.

Conclusion

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.