Methicillin-resistant Staphylococcus aureus (MRSA) infections have seen an increase and persistence in hospital and community settings due to mutations that render them resistant to commonly used antimicrobials. DNA gyrase and Topo IV are type II topoisomerases which regulate supercoiling of DNA driven by ATP hydrolysis. They are essential enzymes involved in bacteria replication. Using Shape Signatures screening, followed by receptor docking onto ATP binding site in crystallographic gyrase B, we were able to uncover a 5-methyl-5-deaza folate analog with high docking score, and a good interaction energy profile from molecular dynamics simulations. One of the analogs makes a hydrogen bond with ASP 81 throughout the course of the simulation. Interaction with this residue has been commonly found in potent Gyr inhibitors such as Novobiocin. ADME predictions suggest a good bioavailability and safety profile. Molecules in this class have previously shown antiplasmodium and antineoplastic activity as folate inhibitors. Following compound synthesis, the antimicrobial activity of the 5-methyl-5-deaza folate analogs are being determined through sensitivity assays by elucidating their minimal inhibitory concentrations against ISP 794 and RN4220 strains of S.aureus. Relaxation assays will be performed to confirm inhibition of DNA gyrase and/or Topo IV activity. Evidence of ATPase activity will be evaluated through phosphate detection assays.

Synthesis and evaluation of 5-methyl-5-deaza folate analogs activity against <i>Staphylococcus aureus </i>type II topoisomerases

247th National Meeting (2014)

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Synthesis and evaluation of 5-methyl-5-deaza folate analogs activity against Staphylococcus aureus type II topoisomerases