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.

天然异戊烯基查尔酮异巴伐查尔酮 ( IBC ) 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。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-hydroxy-pyridin-4(1 H )-one-isobavachalcone 偶联物。偶联物对铜绿假单胞菌的最小抑制浓度 (MIC) 降低 8 至 32 倍，半抑制浓度 (IC ₅₀ s)降低 32 至 177 倍PAO1 以及临床多药耐药 (MDR) 菌株与铁限制下的亲本IBC相比。进一步的研究表明，在不同的铁浓度条件下，结合物的抗菌活性受细菌铁摄取途径的调节。结合物1b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1b对 Vero 细胞的细胞毒性作用低于IBC，并且在治疗由革兰氏阴性菌 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IBC与 3-hydroxy-pyridin-4(1H)-ones 作为铁载体结合后可传递给革兰氏阴性菌，为开发针对革兰氏阴性菌的有效抗菌药物提供了科学依据。