yycF/G as a drug target in emerging zoonotic pathogen Streptococcus suis

Two-component systems (TCSs) are used by bacteria to efficiently adapt to environmental changes such as temperature, osmolarity, chemo-attractants and pH. They are the main system for signal transduction in bacteria. TCSs consist of a histidine kinase (HK), which functions as a sensor, and a response regulator (RR), which regulates the expression of its target genes.

The TCS YycFG is conserved in most Gram-positive bacteria, including a number of important animal and human pathogens.  YycFG is essential for viability and appears to regulate different sets of genes in each species, although genes involved in cell wall metabolism are commonly part of the regulon.  Moreover, YycFG is typically associated with the regulation of virulence.
Therefore, YycFG is a highly attractive drug target for a number of important bacteria including Streptococcus suis, a major bacterial pathogen of swine that causes high mortality and economic losses, requiring frequent use of antibiotics. S. suis is considered worldwide to be a problem for pig industry but it is also emerging as an important cause of meningitis in humans in South East and East Asia.
The aim of this study is to reveal the structure and function of this putative essential TCS in S. suis. YycF, YycG and YycJ proteins and some of their protein domains will be expressed and purified for crystallization and X-ray crystallography. Potential inhibitors of YycF, YycG and YycJ will be identified using docking tools in silico and tested in biochemical assays. In addition, a mariner T7 transposon library of S. suis is used for genome-wide screening using a Tn-seq approach to validate YycFG as an essential TCS and identify (conditionally) essential TCSs as well as other new candidate drug targets. Moreover, knock-outs of virulence genes of S. suis will be created to check their potential as drug targets.