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.
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.
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Zheng
Z
Hou
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Ying
Y
Zhou
School of Chemical Engineering, Xi'an University, Xi'an, Shaanxi, 710065, China.
Jing
J
Li
School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Xinlei
X
Zhang
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Xin
X
Shi
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Xiaoyan
X
Xue
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Zhi
Z
Li
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Bo
B
Ma
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Yukun
Y
Wang
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Mingkai
M
Li
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Xiaoxing
X
Luo
D015110:4-Hydroxycoumarins / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D018805:Sepsis / Q000188:drug therapy / Q000662:veterinary; D013211:Staphylococcus aureus / Q000187:drug effects; D013212:Staphylococcus epidermidis / Q000187:drug effects
D015110:4-Hydroxycoumarins; D000900:Anti-Bacterial Agents; D004258:DNA Polymerase III; C068805:4-hydroxycoumarin