DNA Binding Ligands Targeting Drug-Resistant Bacteria:  Structure, Activity, and Pharmacology

• Published in: Journal of medicinal chemistry Vol. 46; no. 18; pp. 3914 - 3929
• Main Authors: Kaizerman, Jacob A, Gross, Matthew I, Ge, Yigong, White, Sarah, Hu, Wenhao, Duan, Jian-Xin, Baird, Eldon E, Johnson, Kirk W, Tanaka, Richard D, Moser, Heinz E, Bürli, Roland W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.08.2003; Amer Chemical Soc
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Chemistry, Medicinal; Distamycins - chemical synthesis; Distamycins - chemistry; Distamycins - pharmacology; DNA - chemistry; Drug Resistance, Bacterial; Female; Gram-Positive Bacteria - drug effects; Life Sciences & Biomedicine; Ligands; Medical sciences; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - pharmacology; Peritonitis - drug therapy; Peritonitis - microbiology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Science & Technology; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Structure-Activity Relationship; Toxicity Tests, Acute; DISTAMYCIN; ANALOGS; ACIDS; STAPHYLOCOCCUS-AUREUS; AGENTS; IMIDAZOLE; DERIVATIVES; Enterococcus faecalis; Nylon; Intravenous administration; Oligopeptides; Nitrogen heterocycle; Ligand; Toxicity; Pyrrole derivative polymer; Molecular interaction; Vancomycin; Morpholine derivatives; Meticillin; Structure activity relation; Penicillin; Bacteria; Micrococcales; Micrococcaceae; Chemical synthesis; Peritonitis; Staphylococcus aureus; Trimer; Minor groove; Acute; Rodentia; In vitro; Streptococcus pneumoniae; Infection; Resistance; Streptococcaceae; In vivo; Vertebrata; Chemotherapy; Biological fixation; Sulfur heterocycle; Mammalia; Bolus injection; Treatment; Mouse; Abdominal disease; Animal; DNA; Bacteriosis; Antibacterial agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030097a

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 μg/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 ED50 value of 30 mg/kg.