Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Sciences, Lanzhou, China.
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China.
Int J Antimicrob Agents. 2024 Nov;64(5):107338. doi: 10.1016/j.ijantimicag.2024.107338. Epub 2024 Sep 16.
Antibiotic resistance poses a considerable worldwide concern, particularly in clinical environments where drug-resistant Gram-negative bacteria like Klebsiella pneumoniae (K. pneumoniae) present a major challenge. The objective of this research was to investigate the mechanisms by which isobavachalcone (IBC) restores the sensitivity of K. pneumoniae to colistin in vitro and to validate the synergistic therapeutic effect in vivo.
The results indicate that the combined administration of colistin and IBC exhibits a potent antibacterial effect both in vitro and in vivo. The in vitro concurrent administration of colistin and IBC resulted in increased membrane permeability, compromised cell integrity, diminished membrane fluidity, and disrupted membrane homeostasis. Additionally, this combination reduced biofilm production, inhibited the synthesis of the autoinducer factor, altered membrane potential, and affected levels of reactive oxygen species and adenosine triphosphate synthesis, ultimately leading to bacterial death. In vivo experiments on Galleria mellonella and mice demonstrated that the co-administration of colistin and IBC increased the survival rate and significantly reduced pathological damage compared to colistin alone.
These results suggested that IBC effectively restores the sensitivity of colistin by inducing physical disruption of bacterial membranes and oxidative stress. The combination therapy of colistin and IBC presents a viable and safe strategy to combat drug-resistant K. pneumoniae-associated infections.
抗生素耐药性是一个全球性的重大问题，特别是在临床环境中，像肺炎克雷伯菌（K. pneumoniae）这样的耐药革兰氏阴性菌是一个主要挑战。本研究的目的是研究异甘草素（IBC）如何在体外恢复肺炎克雷伯菌对黏菌素的敏感性，并验证体内协同治疗效果。
结果表明，黏菌素和 IBC 的联合给药在体外和体内均具有强大的抗菌作用。体外同时给予黏菌素和 IBC 导致膜通透性增加、细胞完整性受损、膜流动性降低和膜内稳态破坏。此外，这种组合减少了生物膜的产生，抑制了自动诱导因子的合成，改变了膜电位，并影响了活性氧和三磷酸腺苷合成的水平，最终导致细菌死亡。在大蜡螟和小鼠的体内实验中，与单独使用黏菌素相比，联合使用黏菌素和 IBC 可提高生存率并显著减少病理损伤。
这些结果表明，IBC 通过诱导细菌膜的物理破坏和氧化应激，有效恢复了黏菌素的敏感性。黏菌素和 IBC 的联合治疗为治疗耐药性肺炎克雷伯菌相关感染提供了一种可行且安全的策略。
