Infectious Disease Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Jeppiaar Nagar, Rajiv Gandhi Salai, Chennai, 600119, Tamil Nadu, India.
Infectious Disease Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Jeppiaar Nagar, Rajiv Gandhi Salai, Chennai, 600119, Tamil Nadu, India.
Microbiol Res. 2021 Mar;244:126666. doi: 10.1016/j.micres.2020.126666. Epub 2020 Dec 3.
β-lactamase inhibitors are potent synergistic drugs to deteriorate the multidrug-resistant bacteria. Here, we report the β-lactamase inhibitory ability of kalafungin isolated from a marine sponge derived Streptomyces sp. SBRK1. The IC value of the kalafungin was calculated as 225.37 ± 1.95 μM against β-lactamase. The enzyme kinetic analysis showed the Km value of 3.448 ± 0.7 μM and V value of 215.356 ± 8 μM/min and the inhibition mechanism was identified as uncompetitive type. Along with the antibacterial activity, the cell surface analysis of kalafungin treated Staphylococcus aureus cells revealed destruction of cell membrane in response to β-lactamase inhibition. Molecular docking studies have confirmed the binding property of kalafungin against β-lactamase with two hydrogen bonds. In vivo efficacy studies in the zebrafish model by green fluorescent protein expressing S. aureus infection, survival, safety and behavioral profile were reported. The toxicity and anti-infection revealed that the compound was evidently active and safe to all organs. In conclusion, this is the first report on kalafungin with β- lactamase inhibition and suggests that kalafungin may useful for synergic antibacterial therapy with β-lactam drugs to overcome β-lactamase-based resistance of any bacterial pathogens.
β-内酰胺酶抑制剂是一种强效协同药物，可以使多种耐药菌恶化。在这里，我们报告了从海洋海绵衍生的链霉菌 SBRK1 中分离出的卡拉fungin 的β-内酰胺酶抑制能力。卡拉fungin 的 IC 值计算为 225.37 ± 1.95 μM 对β-内酰胺酶。酶动力学分析表明，Km 值为 3.448 ± 0.7 μM，V 值为 215.356 ± 8 μM/min，抑制机制为非竞争性。随着抗菌活性，卡拉fungin 处理的金黄色葡萄球菌细胞的表面分析显示，细胞膜在β-内酰胺酶抑制作用下被破坏。分子对接研究证实了卡拉fungin 与β-内酰胺酶的结合特性，具有两个氢键。通过表达绿色荧光蛋白的金黄色葡萄球菌感染的斑马鱼模型进行体内疗效研究，报告了生存、安全性和行为特征。毒性和抗感染表明，该化合物对所有器官均具有明显的活性和安全性。总之，这是首次报道卡拉fungin 具有β-内酰胺酶抑制作用，并表明卡拉fungin 可能有助于与β-内酰胺类药物协同抗菌治疗，以克服任何细菌病原体的基于β-内酰胺酶的耐药性。
