Graduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brazil.
Department of Analytical and Physical Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil.
Microb Pathog. 2022 Sep;170:105697. doi: 10.1016/j.micpath.2022.105697. Epub 2022 Aug 1.
The prevalence of multidrug-resistant (MDR) bacteria and the limited efficacy of current available antibiotics cause every year approximately 700 000 deaths per year. This study aimed to evaluate the anti-inflammatory effect and antibacterial potential of the ibuprofen derivative Methyl 2-(-4-isobutylphenyl)propanoate (MET-IBU). The molecular structure of MET-IBU was confirmed by Nuclear Magnetic Resonance (NMR) and, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) spectroscopy. Our in vivo study using adult zebrafish model demonstrated that the ibuprofen derivative MET-IBU also possesses anti-inflammatory effect, and in vitro antibacterial activity assays showed that in the association of ampicillin, norfloxacin, and gentamicin with MET-IBU occurred reduction in the minimum inhibitory concentration (MIC) for MDR bacterial strains of Escherichia coli 06 and Staphylococcus aureus 10, indicating a potentiating in the growth inhibition of these pathogenic bacteria. Regarding the strain of Staphylococcus aureus K2068 (overexpressing mepA gene), a potentiation of ethidium bromide was found in the association with MET-IBU, indicating the action of this compound on the efflux pump mechanism present in this strains. This result corroborates the molecular docking study that indicated a high affinity of the MET-IBU with the MepA efflux pump. It was also noticed an antibiotic potentiating activity in the association MET-IBU with norfloxacin against strains of Staphylococcus aureus 1199B (overexpressing norA gene) when compared to the norfloxacin control. This enhanced antibiotic effect of MET-IBU is associated with a second resistance mechanism, which is due to the modification in the topoisomerase enzyme. These results bring attention to the ibuprofen derivative MET-IBU as possible candidate for the development of new options for the treatment of bacterial infections with protective anti-inflammatory action.
多药耐药（MDR）细菌的流行和现有抗生素疗效有限，导致每年约有 70 万人死亡。本研究旨在评估布洛芬衍生物 2-（-4-异丁基苯基）丙酸甲酯（MET-IBU）的抗炎作用和抗菌潜力。通过核磁共振（NMR）和衰减全反射傅里叶变换红外光谱（ATR-FTIR）光谱证实了 MET-IBU 的分子结构。我们使用成年斑马鱼模型的体内研究表明，布洛芬衍生物 MET-IBU 也具有抗炎作用，体外抗菌活性测定表明，在与氨苄西林、诺氟沙星和庆大霉素联合使用时，MET-IBU 降低了多药耐药大肠杆菌 06 和金黄色葡萄球菌 10 的最小抑菌浓度（MIC），表明对这些致病菌的生长抑制作用增强。对于金黄色葡萄球菌 K2068（过度表达 mepA 基因）菌株，与 MET-IBU 联合使用时发现溴化乙锭增效，表明该化合物对该菌株中存在的外排泵机制的作用。这一结果与分子对接研究结果一致，表明 MET-IBU 与 MepA 外排泵具有很高的亲和力。还注意到 MET-IBU 与诺氟沙星联合使用对金黄色葡萄球菌 1199B（过度表达 norA 基因）菌株具有抗生素增效活性，与诺氟沙星对照相比。MET-IBU 的这种增强抗生素作用与第二种耐药机制有关，这是由于拓扑异构酶酶的修饰。这些结果表明，布洛芬衍生物 MET-IBU 可能成为开发新的细菌感染治疗选择的候选药物，具有保护抗炎作用。
