Chemistry and Chemical Biology Works

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Browsing Chemistry and Chemical Biology Works by Author "Aiello, Daniel"

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    DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics
    (American Society for Microbiology, 2016-11-21) Opperman, Timothy J.; Kwasny, Steven M.; Bo Li, Jessica; Lewis, Mark A.; Aiello, Daniel; Williams, John D.; Peet, Norton P.; Moir, Donald T.; Bowlin, Terry L.; Long, Eric C.; Chemistry and Chemical Biology, School of Science
    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 of E. coli and S. aureus to 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 in S. 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.