Abstract：
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.
摘要：
天然的异戊烯化查尔酮异巴卡西酮（IBC）对革兰氏阳性细菌具有良好的抗菌活性，但对革兰氏阴性细菌无效。很可能是由于革兰氏阴性细菌的外膜屏障。特洛伊木马策略已被证明是克服革兰氏阴性细菌外膜渗透性降低的有效策略。在这项研究中,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（1H）-酮-异巴瓦查酮偶联物。与母体IBC相比，缀合物对铜绿假单胞菌PAO1以及临床多药耐药（MDR）菌株的最低抑制浓度（MIC）低8至32倍，半抑制浓度（IC50）低32至177倍。铁限制。进一步研究表明，在不同铁浓度条件下，偶联物的抗菌活性受细菌铁摄取途径的调控。对缀合物1b的抗菌机制研究表明，它通过破坏细胞质膜完整性和抑制细胞代谢而发挥抗菌活性。最后,缀合物1b对Vero细胞的细胞毒性作用低于IBC，在治疗革兰氏阴性菌PAO1引起的细菌感染方面具有积极的治疗作用。总的来说,这项工作表明，当与3-羟基-吡啶-4（1H）-酮作为铁载体结合时，IBC可以传递给革兰氏阴性菌，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。
