DNA binding ligands targeting drug-resistant bacteria: structure, activity, and pharmacology

Jacob A Kaizerman; Matthew I Gross; Yigong Ge; Sarah White; Wenhao Hu; Jian-Xin Duan; Eldon E Baird; Kirk W Johnson; Richard D Tanaka; Heinz E Moser; Roland W Bürli

doi:10.1021/jm030097a

DNA binding ligands targeting drug-resistant bacteria: structure, activity, and pharmacology

J Med Chem. 2003 Aug 28;46(18):3914-29. doi: 10.1021/jm030097a.

Authors

Jacob A Kaizerman¹, Matthew I Gross, Yigong Ge, Sarah White, Wenhao Hu, Jian-Xin Duan, Eldon E Baird, Kirk W Johnson, Richard D Tanaka, Heinz E Moser, Roland W Bürli

Affiliation

¹ Genesoft Pharmaceuticals, Inc., 7300 Shoreline Court, South San Francisco, California 94080, USA.

PMID: 12930152
DOI: 10.1021/jm030097a

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
DNA / chemistry*
Distamycins / chemical synthesis*
Distamycins / chemistry
Distamycins / pharmacology
Drug Resistance, Bacterial*
Female
Gram-Positive Bacteria / drug effects
Ligands
Mice
Mice, Inbred ICR
Microbial Sensitivity Tests
Morpholines / chemical synthesis*
Morpholines / chemistry
Morpholines / pharmacology
Peritonitis / drug therapy
Peritonitis / microbiology
Pyrroles / chemical synthesis*
Pyrroles / chemistry
Pyrroles / pharmacology
Staphylococcal Infections / drug therapy
Staphylococcal Infections / microbiology
Staphylococcus aureus
Structure-Activity Relationship
Toxicity Tests, Acute

Substances

4-(2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(3-chlorothiophene-2-carboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido)ethyl)morpholine
Anti-Bacterial Agents
Distamycins
Ligands
Morpholines
Pyrroles
stallimycin
DNA