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  • Title: DNA binding ligands targeting drug-resistant bacteria: structure, activity, and pharmacology.
    Author: Kaizerman JA, Gross MI, Ge Y, White S, Hu W, Duan JX, Baird EE, Johnson KW, Tanaka RD, Moser HE, Bürli RW.
    Journal: J Med Chem; 2003 Aug 28; 46(18):3914-29. PubMed ID: 12930152.
    Abstract:
    We describe the lead optimization and structure-activity relationship of DNA minor-groove binding ligands, a novel class of antibacterial molecules. These compounds have been shown to target A/T-rich sites within the bacterial genome and, as a result, inhibit DNA replication and RNA transcription. The optimization was focused on N-terminal aromatic heterocycles and C-terminal amines and resulted in compounds with improved in vivo tolerability and excellent in vitro antibacterial potency (MIC >/= 0.031 microg/mL) against a broad range of Gram-positive pathogens, including drug-resistant strains such as methicillin-resistant Stapylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus faecalis (VRE). In a first proof-of-concept study, a selected compound (35) showed in vivo efficacy in a mouse peritonitis model against methicillin-sensitive S. aureus infection with an ED(50) value of 30 mg/kg.
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