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

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3-Hydroxy-pyridin-4(1H)-ones as siderophores mediated delivery of isobavachalcone enhances antibacterial activity against pathogenic Pseudomonas aeruginosa
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2023-05-16 , DOI: 10.1016/j.ejmech.2023.115454
Yong-Jun Huang ₁ , Xiao-Lin Zhong ₁ , Yi-Peng Zang ₁ , Ming-Han Yang ₁ , Jing Lin ₁ , Wei-Min Chen ₁

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The natural prenylated chalcone isobavachalcone () 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(1)-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 (ICs) against PAO1 as well as clinical multidrug-resistant (MDR) strains compared to the parent 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 showed that it exerts antibacterial activity by disrupting cytoplasmic membrane integrity and inhibiting cell metabolism. Finally, conjugate showed a lower cytotoxic effects on Vero cells than and a positive therapeutic effect in the treatment of bacterial infections caused by Gram-negative bacteria PAO1. Overall, this work demonstrates that 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.

中文翻译：

3-羟基-吡啶-4(1H)-酮作为铁载体介导的异罂粟查耳酮的递送增强对致病性铜绿假单胞菌的抗菌活性

天然异戊烯化查耳酮异罂粟查尔酮 (isobavachalcone) 对革兰氏阳性菌表现出良好的抗菌活性，但对革兰氏阴性菌无效，这很可能是由于革兰氏阴性菌的外膜屏障所致。特洛伊木马策略已被证明是克服革兰氏阴性菌外膜通透性降低的有效策略。在本研究中，基于铁载体特洛伊木马策略，设计并合成了八种不同的3-羟基-吡啶-4(1)-one-异补骨脂查耳酮缀合物。与铁剂下的母体相比，该缀合物对 PAO1 以及临床多重耐药 (MDR) 菌株的最低抑制浓度 (MIC) 降低 8 至 32 倍，半抑制浓度 (IC) 降低 32 至 177 倍局限性。进一步的研究表明，在不同铁浓度条件下，缀合物的抗菌活性受到细菌铁摄取途径的调节。结合物的抗菌机制研究表明，其通过破坏细胞质膜完整性、抑制细胞代谢发挥抗菌活性。最后，结合物对 Vero 细胞的细胞毒性作用低于革兰氏阴性菌 PAO1 引起的细菌感染，并具有积极的治疗作用。总体而言，这项工作表明，当与作为铁载体的3-羟基-吡啶-4(1H)-酮结合时，可以将其递送至革兰氏阴性菌，并为开发针对革兰氏阴性菌的有效抗菌剂提供了科学依据。

更新日期：2023-05-16

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