Details

Autor(en) / Beteiligte

• Huang, Yong-Jun
• Zhong, Xiao-Lin
• Zang, Yi-Peng
• Yang, Ming-Han
• Lin, Jing
• Chen, Wei-Min

Titel

3-Hydroxy-pyridin-4(1H)-ones as siderophores mediated delivery of isobavachalcone enhances antibacterial activity against pathogenic Pseudomonas aeruginosa

Ist Teil von

• European journal of medicinal chemistry, 2023-09, Vol.257, p.115454-115454, Article 115454

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The natural prenylated chalcone isobavachalcone (IBC) shows good antibacterial activity against Gram-positive bacteria but is ineffective against Gram-negative bacteria, most likely due to the outer membrane barrier of Gram-negative bacteria. The Trojan horse strategy has been shown to be an effective strategy to overcome the reduction in the permeability of the outer membrane of Gram-negative bacteria. In this study, eight different 3-hydroxy-pyridin-4(1H)-one-isobavachalcone conjugates were designed and synthesized based on the siderophore Trojan horse strategy. The conjugates exhibited 8- to 32-fold lower minimum inhibitory concentrations (MICs) and 32- to 177-fold lower half-inhibitory concentrations (IC50s) against Pseudomonas aeruginosa PAO1 as well as clinical multidrug-resistant (MDR) strains compared to the parent IBC under iron limitation. Further studies showed that the antibacterial activity of the conjugates was regulated by the bacterial iron uptake pathway under different iron concentration conditions. Studies on the antibacterial mechanism of conjugate 1b showed that it exerts antibacterial activity by disrupting cytoplasmic membrane integrity and inhibiting cell metabolism. Finally, conjugate 1b showed a lower cytotoxic effects on Vero cells than IBC and a positive therapeutic effect in the treatment of bacterial infections caused by Gram-negative bacteria PAO1. Overall, this work demonstrates that IBC can be delivered to Gram-negative bacteria when combined with 3-hydroxy-pyridin-4(1H)-ones as siderophores and provides a scientific basis for the development of effective antibacterial agents against Gram-negative bacteria. [Display omitted] •3-Hydroxy-pyridin-4(1H)-one-isobavachalcone conjugates were synthesized.•3-Hydroxy-pyridin-4(1H)-ones can deliver isobavachalcone into the Pseudomonas aeruginosa.•3-Hydroxy-pyridin-4(1H)-ones as siderophores can enhance the antibacterial activity of isobavachalcone.•3-Hydroxy-pyridin-4(1H)-one-isobavachalcone conjugates showed lower toxicity.•3-Hydroxy-pyridin-4(1H)-one-isobavachalcone conjugates could cause bacterial membrane disruption.