Tang Yuanyuan, Deng Han, Xu Zhichao, Yu Zhijian, Xiang Yong, Wen Zewen, Han Shiqing, Chen Zhong, Hou Tieying
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, China.
Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518060, China.
BMC Microbiol. 2025 Jul 2;25(1):393. doi: 10.1186/s12866-025-04104-2.
infections have emerged as a global public health threat. Two key factors—drug resistance and biofilm formation—substantially impair the efficacy of the antimicrobial treatment for infections using conventional antibiotics. Consequently, discovering novel antimicrobial agents with potent antibacterial and antibiofilm activity has become a hotspot in recent years. Herein, the research first reported the remarkable inhibitory activity of AZD-5991, a selective Mcl-1 inhibitor, against . The MIC and MIC values of AZD-5991 against were 12.5 µM, and significant growth inhibition was observed at a subinhibitory concentration of 1/2 × MIC. Additionally, AZD-5991 exhibited bactericidal activity and a robust capacity for inhibiting biofilm formation, with minimal cytotoxicity toward host cell lines. Membrane permeability assays revealed that AZD-5991 compromised cell membrane integrity, while bacterial phospholipid components were found to neutralize the antibacterial activity of AZD-5991. Moreover, whole-genome sequencing and proteomic analysis were also applied to gain insights into the possible impact of AZD-5991 on the fatty metabolism of . Furthermore, the antibacterial activity of AZD-5991 was remarkably declined by exogenous fatty acids linoleic acid (C18:2Δ9,12) and arachidonic acid (C20:4Δ5,8,11,14). Lastly, the biolayer interferometry assay supported the direct interaction of AZD-5991 with FabI, a key protein essential for bacterial growth and fatty acid metabolism. Conclusively, this study demonstrates that AZD-5991 inhibits planktonic growth and biofilm formation by disrupting cell membrane integrity and targeting FabI. These findings position AZD-5991 as a promising novel antibiotic candidate for treating infections resistant to traditional clinical antibiotics.
[Image: see text]
The online version contains supplementary material available at 10.1186/s12866-025-04104-2.
感染已成为全球公共卫生威胁。耐药性和生物膜形成这两个关键因素严重削弱了使用传统抗生素治疗感染的抗菌疗效。因此，近年来发现具有强大抗菌和抗生物膜活性的新型抗菌剂已成为一个热点。在此，该研究首次报道了选择性Mcl-1抑制剂AZD-5991对[具体细菌名称未给出]具有显著的抑制活性。AZD-5991对[具体细菌名称未给出]的MIC和MIC值为12.5μM，在1/2×MIC的亚抑制浓度下观察到显著的生长抑制。此外，AZD-5991表现出杀菌活性和强大的抑制[具体细菌名称未给出]生物膜形成的能力，对宿主细胞系的细胞毒性最小。膜通透性测定表明AZD-5991破坏了[具体细菌名称未给出]细胞膜的完整性，而细菌磷脂成分被发现可中和AZD-5991的抗菌活性。此外，还应用了全基因组测序和蛋白质组学分析来深入了解AZD-5991对[具体细菌名称未给出]脂肪酸代谢的可能影响。此外，外源性脂肪酸亚油酸（C18:2Δ9,12）和花生四烯酸（C20:4Δ5,8,11,14）显著降低了AZD-5991的抗菌活性。最后，生物层干涉测定法支持AZD-5991与FabI直接相互作用，FabI是细菌生长和脂肪酸代谢所必需的关键蛋白质。总之，本研究表明AZD-5991通过破坏细胞膜完整性和靶向FabI来抑制[具体细菌名称未给出]的浮游生长和生物膜形成。这些发现使AZD-5991成为治疗对传统临床抗生素耐药的[具体细菌名称未给出]感染的有前景的新型抗生素候选物。
[图像：见正文]
在线版本包含可在10.1186/s12866-025-04104-2获取的补充材料。
