DNA binding ligands with improved in vitro and in vivo potency against drug-resistant Staphylococcus aureus.
Potent in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA) has been difficult to achieve with previously reported DNA binding antibacterials. Herein, we describe an efficient access to a focused library of new analogues yielding compounds with improved activity in a mouse peritonitis model. The most potent molecules (14 and 19) exhibit efficacy against MRSA at ED50 values of approximately 1 and approximately 5 mg/kg, respectively, and display excellent in vitro activity against vancomycin-resistant S. aureus.
Genesoft Pharmaceuticals, Inc., 7300 Shoreline Court, South San Francisco, California 94080, USA.
Wenhao
W
Hu
Roland W
RW
Bürli
Jacob A
JA
Kaizerman
Kirk W
KW
Johnson
Matthew I
MI
Gross
Mari
M
Iwamoto
Peter
P
Jones
Denene
D
Lofland
Stacey
S
Difuntorum
Hsiu
H
Chen
Bülent
B
Bozdogan
Peter C
PC
Appelbaum
Heinz E
HE
Moser
D000818:Animals; D004247:DNA / Q000378:metabolism; D004214:Distamycins / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D007700:Kinetics; D008024:Ligands; D008712:Methicillin; D051379:Mice; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014640:Vancomycin
D004214:Distamycins; D008024:Ligands; D014640:Vancomycin; D004247:DNA; D008712:Methicillin