Life Science Research Center, Universidad Simón Bolívar, Barranquilla 080002, Colombia.
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
Int J Mol Sci. 2022 Jan 31;23(3):1630. doi: 10.3390/ijms23031630.
Bacterial resistance is responsible for a wide variety of health problems, both in children and adults. The persistence of symptoms and infections are mainly treated with β-lactam antibiotics. The increasing resistance to those antibiotics by bacterial pathogens generated the emergence of extended-spectrum β-lactamases (ESBLs), an actual public health problem. This is due to rapid mutations of bacteria when exposed to antibiotics. In this case, β-lactamases are enzymes used by bacteria to hydrolyze the beta-lactam rings present in the antibiotics. Therefore, it was necessary to explore novel molecules as potential β-lactamases inhibitors to find antibacterial compounds against infection caused by ESBLs. A computational methodology based on molecular docking and molecular dynamic simulations was used to find new microalgae metabolites inhibitors of β-lactamase. Six 3D β-lactamase proteins were selected, and the molecular docking revealed that the metabolites belonging to the same structural families, such as phenylacridine (4-Ph), quercetin (Qn), and cryptophycin (Cryp), exhibit a better binding score and binding energy than commercial clinical medicine β-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam. These results indicate that 4-Ph, Qn, and Cryp molecules, homologous from microalgae metabolites, could be used, likely as novel β-lactamase inhibitors or as structural templates for new in-silico pharmaceutical designs, with the possibility of combatting β-lactam resistance.
细菌耐药性是儿童和成人多种健康问题的根源。针对持续性症状和感染，主要使用β-内酰胺类抗生素进行治疗。由于细菌病原体对这些抗生素的耐药性不断增加，产生了超广谱β-内酰胺酶（ESBLs），这是一个实际存在的公共卫生问题。这是由于细菌在接触抗生素时会迅速发生突变。在这种情况下，β-内酰胺酶是细菌用来水解抗生素中β-内酰胺环的酶。因此，有必要探索新型分子作为潜在的β-内酰胺酶抑制剂，以寻找针对 ESBLs 感染的抗菌化合物。本研究采用基于分子对接和分子动力学模拟的计算方法，寻找新的微藻代谢物β-内酰胺酶抑制剂。选择了 6 种 3D β-内酰胺酶蛋白，分子对接结果表明，属于同一结构家族的代谢物，如苯基吖啶（4-Ph）、槲皮素（Qn）和隐色菌素（Cryp），其结合评分和结合能优于商用临床β-内酰胺酶抑制剂，如克拉维酸、舒巴坦和他唑巴坦。这些结果表明，微藻代谢物同源的 4-Ph、Qn 和 Cryp 分子可能被用作新型β-内酰胺酶抑制剂或新型药物设计的结构模板，从而有希望对抗β-内酰胺耐药性。
