Biology Reference
In-Depth Information
Chapter 7
pneumoniae
Nan Li, Fei Wang, Siqiang Niu, Ju Cao, Kaifeng Wu, Youqiang Li,
Nanlin Yin, Xuemei Zhang, Weiliang Zhu, and Yibing Yin
INTRODUCTION
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.
Using a structure-based virtual screening (SBVS) method, 105 compounds were
computationally identifi ed 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 mor-
tality of the mice infected by
S. pneumoniae
and one compound even has signifi cant
therapeutic effect.
To our knowledge, these compounds are the fi rst 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.
Streptococcus pneumoniae
is a major risk factor with high morbidity and mortal-
ity world-widely, especially in the elderly and children. It is believed to be one of
the four major infectious disease killers [1-5]. Meanwhile, an increasing number of
bacterial strains with resistance are encountered in the clinic nowadays, among which
antibiotic-resistant
S. pneumoniae
has caused many deaths due to antibiotics abusage
in hospitals. Therefore, it is urgent to develop new types of antibiotics.
In prokaryotes, the two-component signaling systems, each pair of which are
typically composed of HK and response regulator (RR), play important roles in drug-
resistance, pathogenesis and bacterial growth [6-8]. The regulation of TCS on histi-
dine phosphorylation in signal transduction distinct from that on serine/threonine and
tyrosine phosphorylation in higher eukaryotes [9]. For some TCSs, both the HK and
RR are essential for bacterial viability in several Gram-positive pathogens, includ-
ing
Bacillus subtilis
(
B. subtilis
),
Enterococcus faecalis
and
Staphylococcus aureus
