title: DNA binding ligands targeting drug-resistant bacteria: structure, activity, and pharmacology.
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.
authors.affiliation: Genesoft Pharmaceuticals, Inc., 7300 Shoreline Court, South San Francisco, California 94080, USA.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Kaizerman
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Gross
authors.forename: Yigong
authors.initials: Y
authors.lastname: Ge
authors.forename: Sarah
authors.initials: S
authors.lastname: White
authors.forename: Wenhao
authors.initials: W
authors.lastname: Hu
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Duan
authors.forename: Eldon E
authors.initials: EE
authors.lastname: Baird
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
authors.forename: Richard D
authors.initials: RD
authors.lastname: Tanaka
authors.forename: Heinz E
authors.initials: HE
authors.lastname: Moser
authors.forename: Roland W
authors.initials: RW
authors.lastname: Bürli
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D004214:Distamycins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008024:Ligands; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
chemical_list: C477199:4-(2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(3-chlorothiophene-2-carboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido)ethyl)morpholine; D000900:Anti-Bacterial Agents; D004214:Distamycins; D008024:Ligands; D009025:Morpholines; D011758:Pyrroles; C030000:stallimycin; D004247:DNA