Methicillin resistant S. aureus (MRSA), is among the major drug resistant bacteria and is growing at an alarming rate due to mutations that render them resistant to commonly used antimicrobials. DNA gyrase regulates supercoiling of DNA driven by ATP hydrolysis. It is an essential enzyme involved in bacteria replication. Shape Signatures is a novel molecular screening tool developed in our laboratory, which was used for rapid screening of a large database for agents with similar shape as the known gyrase B inhibitor, Novobiocin. The binding energetics and physico-chemical properties of the top hits from this initial scan were further validated by molecular docking using the GOLD and GLIDE docking tools and their binding stability confirmed through molecular dynamics simulations. Three rhodanine-substituted derivatives had significant antimicrobial activity against S.aureus Carolina and ISP 794 strains, as determined by minimal inhibitory concentration assays, with Novobiocin as the positive control. Biochemical evidence supports the fact that the lead compound decreases the ATPase activity of gyrase. The inhibition of the DNA supercoiling activity of gyrase by these compounds is being evaluated through relaxation assays. Another potential lead identified through docking experiments, which is also a known folate inhibitor, had a promising GLIDE score of -12.64 at the ATP binding pocket of gyrase B.  It made significant backbone hydrogen bonding interactions at the receptor site and thereby may delay bacterial resistance. This compound is currently being synthesized for further in vitro validation of its biochemical and biological activity.

Identification and validation of new topoisomerase type  II inhibitors for the treatment of multi-drug resistance  <i>Staphylococcus aureus</i> through computer-aided drug design

243rd National Meeting (2012)

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Identification and validation of new topoisomerase type II inhibitors for the treatment of multi-drug resistance Staphylococcus aureus through computer-aided drug design