School of Pharmacy, Fudan University, Shanghai 201203, China.
Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, U.K.
ACS Infect Dis. 2023 Aug 11;9(8):1523-1533. doi: 10.1021/acsinfecdis.3c00066. Epub 2023 Jul 7.
Multidrug-resistant , a Gram-positive bacterium that causes several difficult-to-treat human infections, is a considerable threat to global healthcare. We hypothesize that there exist inner responsive molecules (IRMs) which can function synergistically with antibiotics to restore the sensitivity of resistant bacteria to existing antibiotics without inducing new antibiotic resistance. An investigation of the extracts of the Chinese medicinal herb L. led to the isolation of six benzoate esters, -. Among these, as a distinct IRM displayed considerable synergism by potentiating antibacterial activity against five antibiotic-resistant strains. Mechanistic studies demonstrated that acted as a suppressing drug resistance IRM via inhibiting efflux activity. A combination of with ciprofloxacin significantly inhibited resistance to this antibiotic and reversed its resistance in the strain. Furthermore, effectively enhanced the activity of ciprofloxacin against the efflux fluoroquinolone-resistant strain SA1199B that caused infection in two animal models and significantly decreased the inflammatory factors IL-6 and C-reactive protein of the infected mice, thereby showing the practice utility of this approach.
耐多药革兰阳性菌可引起多种难以治疗的人类感染，对全球医疗保健构成重大威胁。我们假设存在内响应分子（IRMs），它们可以与抗生素协同作用，恢复耐药菌对现有抗生素的敏感性，而不会诱导新的抗生素耐药性。对中药 L. 的提取物进行研究，分离得到六种苯甲酸酯， - 。其中， 作为一种独特的 IRM，通过增强对五种抗生素耐药菌株的抗菌活性表现出相当大的协同作用。机制研究表明， 通过抑制外排活性发挥抑制耐药性 IRM 的作用。 与环丙沙星联合使用可显著抑制对该抗生素的耐药性，并使 菌株恢复耐药性。此外， 还能有效增强环丙沙星对引起两种动物模型感染的外排氟喹诺酮耐药 菌株 SA1199B 的活性，并显著降低感染小鼠的炎症因子 IL-6 和 C-反应蛋白，从而显示出这种方法的实际应用价值。
