Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
Department of Medical Lab Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
ACS Infect Dis. 2023 Aug 11;9(8):1634-1646. doi: 10.1021/acsinfecdis.3c00257. Epub 2023 Jul 17.
Being among the few last-resort antibiotics, colistin (COL) has been used to treat severe infectious diseases, such as those caused by multidrug-resistant Gram-negative bacteria (MDR GNB). However, the appearance of colistin-resistant (COL-R) GNB has been frequently reported. Therefore, novel antimicrobial strategies need to be urgently sought to address this resistance challenge. In the present study, antimicrobial drug screening conducted revealed that bithionol (BT), approved by the Food and Drug Administration and used as an anthelminthic drug for paragonimiasis, exhibited a synergistic antibacterial effect with COL. Clinically isolated COL-R GNB were used as candidates to evaluate the synergistic antibacterial activity. The results revealed that BT could significantly reverse the sensitivity of COL-R GNB to COL. Furthermore, the combined application of BT and COL can reduce bacterial biofilm formation and have a scavenging effect on the mature biofilm . The damage caused to the bacterial cell membrane integrity by the BT/COL combination was observed under a fluorescence microscope. The fluorescence intensity of reactive oxygen species also increased in the experimental group. The BT/COL combination also exhibited a synergistic antibacterial effect . Importantly, BT was confirmed to be safe at the highest concentrations that exerted synergistic effects on all tested strains. In conclusion, our findings demonstrated that BT exerted synergistic antimicrobial and anti-biofilm effects when combined with COL against MDR organisms, especially COL-R GNB, and . The findings thus provide a reference for the clinical response to the serious challenge of MDR GNB and the exploitation of the potential antibacterial activities of existing clinical non-antibacterial drugs.
黏菌素（COL）作为少数最后手段的抗生素之一，已被用于治疗严重的传染病，如多药耐药革兰氏阴性菌（MDR GNB）引起的感染。然而，耐黏菌素革兰氏阴性菌（COL-R GNB）的出现频率越来越高。因此，需要紧急寻找新的抗菌策略来应对这种耐药性挑战。在本研究中，通过抗菌药物筛选发现，已获美国食品和药物管理局批准并用于治疗并殖吸虫病的驱虫药双羟萘酸噻嘧啶（BT）与 COL 具有协同抗菌作用。以临床分离的 COL-R GNB 作为候选菌株，评估其协同抗菌活性。结果表明，BT 可显著逆转 COL-R GNB 对 COL 的耐药性。此外，BT 和 COL 的联合应用可减少细菌生物膜的形成，并对成熟生物膜具有清除作用。荧光显微镜下观察到 BT/COL 联合应用可破坏细菌细胞膜完整性。实验组中活性氧的荧光强度也增加。BT/COL 联合应用还表现出协同抗菌作用。重要的是，BT 在对所有测试菌株均发挥协同作用的最高浓度下被证实是安全的。总之，我们的研究结果表明，BT 与 COL 联合使用对 MDR 菌，尤其是 COL-R GNB，具有协同的抗菌和抗生物膜作用。这些发现为临床应对 MDR GNB 的严峻挑战以及开发现有临床非抗菌药物的潜在抗菌活性提供了参考。
