G‑Quadruplex DNA as a Target in Pathogenic Bacteria: Efficacy of an Extended Naphthalene Diimide Ligand and Its Mode of Action

Guanidine DNA quadruplex
(G4-DNA) structures convey a distinctive
layer of epigenetic information that is critical for regulating key
biological activities and processes as transcription, replication,
and repair in living cells. The information regarding their role and
use as therapeutic drug targets in bacteria is still scarce. Here,
we tested the biological activity of a G4-DNA ligand library, based
on the naphthalene diimide (NDI) pharmacophore, against both Gram-positive
and Gram-negative bacteria. For the best compound identified, NDI-10, a different action mechanism was described for Gram-positive
or negative bacteria. This asymmetric activity profile could be related
to the different prevalence of putative G4-DNA structures in each
group, the influence that they can exert on gene expression, and the
different roles of the G4 structures in these bacteria, which seem
to promote transcription in Gram-positive bacteria and repress transcription
in Gram-negatives.