Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Thandalam, 602105, Chennai, Tamil Nadu, India.
Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India.
Microb Pathog. 2024 Nov;196:106968. doi: 10.1016/j.micpath.2024.106968. Epub 2024 Sep 21.
Foodborne pathogens continue to challenge public health due to their ability to cause severe illness and their increasing resistance to current antimicrobial treatments. Listeria monocytogenes is a resilient foodborne pathogen that poses significant risks to vulnerable populations, leading to severe infections and high hospitalization rates. The emergence of antimicrobial-resistant (AMR) strains of L. monocytogenes underscores the need for novel therapeutic strategies. In this study, we investigated the antimicrobial efficacy of the (2E)-3-(3,5-dibromo-2-hydroxylphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one (DK06) against multidrug-resistant L. monocytogenes. DK06 exhibited a significant dose-dependent inhibition of L. monocytogenes growth, achieving a maximum inhibition of 92.9 % at 320 μM. Molecular docking and dynamics simulations revealed high binding affinities for key virulence proteins PlcB and ArgA, with stable protein-ligand interactions. DK06 also disrupted biofilm formation at sub-MIC levels, reducing extracellular polymeric substances (EPS) and biofilm mass, as observed by scanning electron microscopy (SEM) analysis. Furthermore, DK06 downregulated the expression of virulence genes (plcB, argA, and hly) and decreased hemolytic activity. In vivo zebrafish studies confirmed the safety of DK06 up to 80 μM, demonstrating its efficacy in reducing mortality and oxidative stress associated with L. monocytogenes infection. DK06 also attenuated inflammation by downregulating key inflammatory markers (tnfa, il1b, il6, and nfkb). These findings indicate that DK06 is a promising multi-target inhibitor with potential application in treating infections and combating antimicrobial resistance.
食源性病原体由于其引起严重疾病的能力及其对当前抗菌治疗的日益耐药性，继续对公共卫生构成挑战。李斯特菌是一种具有弹性的食源性病原体，对弱势群体构成重大风险，导致严重感染和高住院率。李斯特菌抗药性（AMR）菌株的出现突显了需要新的治疗策略。在这项研究中，我们研究了（2E）-3-（3,5-二溴-2-羟基苯基）-1-（5-甲基呋喃-2-基）-2-丙烯-1-酮（DK06）对多药耐药李斯特菌的抗菌功效。DK06 对李斯特菌的生长表现出显著的剂量依赖性抑制作用，在 320μM 时达到最大抑制率 92.9%。分子对接和动力学模拟显示对关键毒力蛋白 PlcB 和 ArgA 具有高结合亲和力，与稳定的蛋白-配体相互作用。DK06 还在亚 MIC 水平下破坏生物膜形成，减少细胞外聚合物质（EPS）和生物膜质量，通过扫描电子显微镜（SEM）分析观察到。此外，DK06 下调了毒力基因（plcB、argA 和 hly）的表达并降低了溶血活性。体内斑马鱼研究证实了 DK06 高达 80μM 的安全性，表明其在降低与李斯特菌感染相关的死亡率和氧化应激方面的功效。DK06 还通过下调关键炎症标志物（tnfa、il1b、il6 和 nfkb）来减轻炎症。这些发现表明，DK06 是一种有前途的多靶标抑制剂，具有治疗感染和对抗抗菌耐药性的潜在应用。
