DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics.
We previously reported the synthesis and biological activity of a series of cationic bis-indoles with potent, broad-spectrum antibacterial properties. Here, we describe mechanism of action studies to test the hypothesis that these compounds bind to DNA and that this target plays an important role in their antibacterial outcome. The results reported here indicate that the bis-indoles bind selectively to DNA at A/T-rich sites, which is correlated with the inhibition of DNA and RNA synthesis in representative Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) organisms. Further, exposure ofE. coliandS. aureusto representative bis-indoles resulted in induction of the DNA damage-inducible SOS response. In addition, the bis-indoles were found to be potent inhibitors of cell wall biosynthesis; however, they do not induce the cell wall stress stimulon inS. aureus, suggesting that this pathway is inhibited by an indirect mechanism. In light of these findings, the most likely basis for the observed activities of these compounds is their ability to bind to the minor groove of DNA, resulting in the inhibition of DNA and RNA synthesis and other secondary effects.
Microbiotix, Inc., Worcester, Massachusetts, USA topperman@microbiotix.com eclong@iupui.edu.
Timothy J
TJ
Opperman
Microbiotix, Inc., Worcester, Massachusetts, USA.
Steven M
SM
Kwasny
Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA.
Jessica Bo
JB
Li
Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA.
Mark A
MA
Lewis
Microbiotix, Inc., Worcester, Massachusetts, USA.
Daniel
D
Aiello
Microbiotix, Inc., Worcester, Massachusetts, USA.
John D
JD
Williams
Microbiotix, Inc., Worcester, Massachusetts, USA.
Norton P
NP
Peet
Microbiotix, Inc., Worcester, Massachusetts, USA.
Donald T
DT
Moir
Microbiotix, Inc., Worcester, Massachusetts, USA.
Terry L
TL
Bowlin
Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA topperman@microbiotix.com eclong@iupui.edu.
Eric C
EC
Long
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008856:Microscopy, Fluorescence; D058990:Molecular Targeted Therapy; D013014:SOS Response, Genetics / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects
D000900:Anti-Bacterial Agents; D007093:Imidazoles; D007211:Indoles; C000591625:MBX 1066; D004247:DNA