Artem Cherkasov's Biography

• Home
• |
• Agenda
  • Agenda Day 1
  • Agenda Day 2
• |

Chemogenomics-Based Discovery of Novel Pyruvate Kinase Inhibitors for Methicillin-Resistant Staphylococcus aureus (MRSA)

Tuesday, 29 March 2011 at 16:00

Add to Calendar ▼2011-03-29 16:00:002011-03-29 17:00:00Europe/LondonChemogenomics-Based Discovery of Novel Pyruvate Kinase Inhibitors for Methicillin-Resistant Staphylococcus aureus (MRSA)MedChem Europe in MunichMunichSELECTBIOenquiries@selectbiosciences.com

We have recently mapped protein interaction networks of methicillin-resistant Staphylococcus aureus (MRSA). This revealed that the network exhibits scale-free organization with characteristic presence of highly-connected hub proteins that are critical for network integrity and stability. Here we report identification of inhibitors for one such MRSA hub - staphylococcal pyruvate kinase (PK) which are highly selective relative to the mammalian homologs. Computer-aided drug design was utilized to identify several selective, low nanomolar inhibitors for the MRSA PK. Two experimentally resolved structures of tetrameric MRSA PK co-crystallized with the developed antagonists revealed critical details of their inhibitory binding to the interface between the PK subunits. This newly described intra-unit pocket is not present in otherwise highly similar human orthologs and can be effectively utilized for selective inhibition of bacterial protein. Considering a notable lack of recent reports on novel and validated antibacterial targets, the results of the current study may provide a valuable target for development of a new generation of antimicrobial drugs.