Design and Synthesis of Novel Antibacterials
In this work, several small molecules were rationally designed and synthesized with the objective of inhibiting interactions of the PA pre-pore structure of the Bacillus anthracis toxin. The small molecules were designed and synthesized with the potential of being PA heptamerization inhibitors by disrupting key amino acid residues that are important in the protein-protein interaction between PA monomers. The small molecules were tested against PA and LF using the J774A.1 cell line in a MTT-based assay that yielded modest cell rescue activity. Additionally, new antimicrobial scaffolds were designed and synthesized for the selective treatment of MRSA and VRE infections, by inhibiting bacterial class II-HMGR enzyme. Herein the design and synthesis of 24 (5-(N -(4-butylphenyl)sulfamoyl)-2-hydroxybenzoic acid) analogues is reported. Several of the inhibitors showed increased activity, with the best displaying an IC50 of 2 µM against E. faecalis and S. aureus II-HMGR, in the HMG-CoA to mevalonate direction. Interestingly, 10 analogues showed antibacterial activity against MRSA and E. faecalis in an in vitro assay. The most potent antibacterial analogue showed an MIC of 16 µM against MRSA and E. faecalis. The bioactive analogues were found to be not toxic in vitro to murine J774A.1 cells at 50 and 100 µM concentrations. The present study provides a new class of potential antibacterial scaffolds for the selective treatment of MRSA and VRE infections.
Lipton, Purdue University.
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