Selective in vivo and in vitro activities of 3,3′-4-nitrobenzylidene-bis-4-hydroxycoumarin against methicillin-resistant Staphylococcus aureus by inhibition of DNA polymerase III

• Published in: Scientific reports 2015-09, Vol.5 (1), p.13637-13637, Article 13637
• Main Authors: Hou, Zheng, Zhou, Ying, Li, Jing, Zhang, Xinlei, Shi, Xin, Xue, Xiaoyan, Li, Zhi, Ma, Bo, Wang, Yukun, Li, Mingkai, Luo, Xiaoxing
• Format: Article
• Language: English
• Subjects: 4-Hydroxycoumarins - chemistry; 4-Hydroxycoumarins - therapeutic use; 4-Hydroxycoumarins - toxicity; 631/326/41/88; 692/699/255/1318; 692/700/155; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - therapeutic use; Anti-Bacterial Agents - toxicity; Antibacterial activity; Antibacterial agents; Antibiotics; Binding Sites; Cell Line, Tumor; Cell Survival - drug effects; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA polymerase; DNA Polymerase III - antagonists & inhibitors; DNA Polymerase III - metabolism; DNA Replication - drug effects; DNA-directed DNA polymerase; Drug resistance; Hemolysis - drug effects; Humanities and Social Sciences; Humans; Medical innovations; Methicillin; Methicillin-Resistant Staphylococcus aureus - drug effects; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; multidisciplinary; Protein Structure, Tertiary; Science; Sepsis - drug therapy; Sepsis - veterinary; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus epidermidis - drug effects; Staphylococcus infections
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep13637

As the persistent resistance of Staphylococcus aureus to available antibiotics is associated with high infection incidence, mortality rate and treatment cost, novel antibacterial agents with innovative therapeutic targets must be developed. 3,3′-(4-Nitrobenzylidene)-bis-(4-hydroxycoumarin) (NBH), a dicoumarin derivative, was reported to exert antibacterial activity. This study investigated the underlying mechanisms of in vivo and in vitro activities of NBH against S. aureus . NBH exerted bactericidal effects against the tested S. aureus and Staphylococcus epidermidis strains in vitro , with low cytotoxicity and resistance and high plasma stability. NBH also exhibited therapeutic effects in vivo on septicaemic mice. Results of molecular docking and analysis on morphological change, DNA production and polymerase inhibition suggested that DNA polymerase could be the target of NBH. These findings indicated that dicoumarin derivatives, which interfere with DNA replication, could be developed as a potential agent against S. aureus , particularly methicillin-resistant strains.