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 autophosphorylation
in vitro, indicating that they are potential inhibitors of the YycG/YycF twocomponent
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.
Conclusion: 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.