de Araújo-Neto José B, Alves Daniel S, de Araújo Gildênia A, Ribeiro Fernanda R, Brancaglion Guilherme A, Carvalho Diogo T, Coutinho Henrique D M, Schrank Augusto, Tintino Saulo R
Postgraduate Program in Biological Sciences, Biosciences Center, Federal University of Pernambuco, Recife, PE, 50740-570, Brazil.
Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri, Crato, CE, 63105-000, Brazil.
Curr Microbiol. 2025 Jul 30;82(9):422. doi: 10.1007/s00284-025-04397-6.
Drug resistance is a pivotal issue in the treatment of bacterial infections. Thus, discovering alternative drugs is necessary to control antibiotic-resistant bacteria, such as β-lactamase-producing Staphylococcus aureus. Coumarins with C-3 modifications have different inhibitory effects on bacteria, including resistant ones. Here, we evaluate the in vitro and in silico potential of 3-substituted coumarins in inhibiting S. aureus β-lactamase. This study involved assays of antibacterial activity and association with ampicillin to control strains producing β-lactamase, studies of molecular docking with the blaZ-encoded β-lactamase, and analysis of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of 3-substituted coumarins. The derivatives did not inhibit bacterial growth. However, they enhanced the ampicillin activity, reducing the inhibitory concentration by up to 93.75%. Molecular docking revealed the affinity of the compounds to the β-lactamase model and showed that coumarins interact with crucial amino acids for enzymatic activity, such as the Ser70 residue. The ADMET profiles showed favorable predictions and limitations of the derivatives, such as the distribution and higher number of toxicity alerts for coumarins C2 and C3. Therefore, our study highlights the ability of 3-substituted coumarins to inhibit S. aureus β-lactamase and the contribution of C-3 substituents to the resistance modulation and ADMET profile.
耐药性是细菌感染治疗中的一个关键问题。因此，发现替代药物对于控制抗生素耐药菌，如产β-内酰胺酶的金黄色葡萄球菌是必要的。具有C-3修饰的香豆素对包括耐药菌在内的细菌有不同的抑制作用。在此，我们评估了3-取代香豆素在体外和计算机模拟中抑制金黄色葡萄球菌β-内酰胺酶的潜力。本研究包括抗菌活性测定以及与氨苄西林联合用于控制产β-内酰胺酶菌株的实验、与blaZ编码的β-内酰胺酶的分子对接研究，以及对3-取代香豆素的吸收、分布、代谢、排泄和毒性（ADMET）分析。这些衍生物没有抑制细菌生长。然而，它们增强了氨苄西林的活性，将抑制浓度降低了高达93.75%。分子对接揭示了这些化合物与β-内酰胺酶模型的亲和力，并表明香豆素与酶活性的关键氨基酸相互作用，如Ser70残基。ADMET图谱显示了这些衍生物的良好预测结果和局限性，如香豆素C2和C3的分布以及较高数量的毒性警示。因此，我们的研究突出了3-取代香豆素抑制金黄色葡萄球菌β-内酰胺酶的能力以及C-3取代基对耐药性调节和ADMET图谱的贡献。
