Computer-Aided Identification of New DNA Gyrase Inhibitors with Activity against Staphylococcus aureus.

摘要

Methicillin resistant S. aureus (MRSA) is among the major drug resistant bacteria that persist in both the community and clinical settings due to resistance to commonly used antimicrobials. This continues to fuel the need for novel compounds that are active against this organism. In our efforts to find new compounds with activity against S. aureus, we have targeted the type IIA bacterial topoisomerase, DNA Gyrase, an essential enzyme involved in bacterial replication, through the ATP-dependent supercoiling of DNA. The virtual screening tool Shape Signatures was applied to screen a large database for agents with shape similar to Novobiocin, a known gyrase B inhibitor. The binding energetics of the top hits from this initial screen were further validated by molecular docking. Compounds with the highest score against available crystal structure of homologous DNA gyrase from T. Thermophilus were selected. From this initial set of compounds, several rhodanine-substituted derivatives had the highest antimicrobial activity against S. aureus, as determined by minimal inhibitory concentration assays, with Novobiocin as the positive control. Further activity validation of the rhodanine compounds through biochemical assays confirmed their inhibition of both the supercoiling and the ATPase activity of DNA gyrase. Subsequent docking and molecular dynamics on the crystal structure of DNA gyrase from S. aureus when it became available, provides further rationalization of the observed biochemical activity and understanding of the receptor-ligand interactions. In addition, a regression model for minimal inhibitory concentration prediction against S. aureus was generated based on the current molecules studied as well as other rhodanines derivatives found in the literature.