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

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. T...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-08, Vol.46 (18), p.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: Article
Language:English
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
Distamycins - chemical synthesis
Distamycins - chemistry
Distamycins - pharmacology
DNA - chemistry
Drug Resistance, Bacterial
Female
Gram-Positive Bacteria - drug effects
Ligands
Medical sciences
Mice
Mice, Inbred ICR
Microbial Sensitivity Tests
Morpholines - chemical synthesis
Morpholines - chemistry
Morpholines - pharmacology
Peritonitis - drug therapy
Peritonitis - microbiology
Pharmacology. Drug treatments
Pyrroles - chemical synthesis
Pyrroles - chemistry
Pyrroles - pharmacology
Staphylococcal Infections - drug therapy
Staphylococcal Infections - microbiology
Staphylococcus aureus
Structure-Activity Relationship
Toxicity Tests, Acute
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm030097a