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.

胍基DNA四链体（Guanidine DNA quadruplex，G4-DNA）结构承载着一类独特的表观遗传信息，其对于调控活细胞内转录、复制与修复等关键生物学活动与过程至关重要。目前关于这类结构在细菌中的功能以及其作为治疗性药物靶点的应用相关研究仍较为匮乏。本研究针对基于萘二酰亚胺（naphthalene diimide，NDI）药效团构建的G4-DNA配体库，开展了针对革兰氏阳性（Gram-positive）与革兰氏阴性（Gram-negative）细菌的生物学活性测试。针对筛选得到的最优化合物NDI-10，研究发现其对两类细菌的作用机制存在差异。这种不对称活性特征可能与以下因素相关：两类细菌中推定G4-DNA结构的分布差异、其对基因表达的调控作用，以及G4结构在两类细菌中发挥的不同功能——在革兰氏阳性菌中G4结构可促进转录，而在革兰氏阴性菌中则抑制转录。