DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics

Abstract

bWe 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.

Recent developments in compounds acting in the DNA minor groove

“…The synthesis and biological study of amidinium derivatives of bis-indoles (15, Fig. 9) with potent and broadspectrum antibacterial activity have been reported by Opperman et al 71 The results obtained show that these bisindoles are A-T selective MGBs (in vitro and within bacterial cells), which correlates to their power to inhibit DNA and RNA synthesis in Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. It seems that these compounds prompt a DNA damage-inducible SOS response in these bacteria and they are potent inhibitors of cell wall biosynthesis.…”

Resistance-resistant antibiotics

“…Interestingly, small structural changes in bisamidine structure can switch a molecule from targeting cell wall biosynthesis to inhibiting DNA biosynthesis (as deduced from macro-molecular labeling experiments). [68] Specifically, the Microbiotix compound MBX-1066 ( 16 ) with a 5-membered ring inhibits (primarily) DNA biosynthesis, the 6-membered ring homolog (MBX-1162) inhibits cell wall biosynthesis.…”

Synthesis, DFT studies, molecular docking, antimicrobial screening and UV fluorescence studies on ct-DNA for novel Schiff bases of 2-(1-aminobenzyl) benzimidazole

“…Also, small molecules targeting bacterial DNA are the most widely studied due to their better efficacy as drugs. However, their binding modes may vary from either minor groove binding or intercalation depending on selectivity towards specific DNA sequence [3, 4].…”