Alves Borges Leal Antonio Linkoln, Teixeira da Silva Priscila, Nunes da Rocha Matheus, Marinho Emanuelle Machado, Marinho Emmanuel Silva, Marinho Márcia Machado, Bandeira Paulo Nogueira, Sampaio Nogueira Carlos Emidio, Barreto Humberto Medeiros, Rodrigues Teixeira Alexandre Magno, Silva Dos Santos Hélcio
Department of Biological Chemistry, Regional University of Cariri, Crato, Ceará, Brazil; Department of Parasitology and Microbiology, Federal University of Piaui, Teresina, Piaui, Brazil.
Department of Biological Chemistry, Regional University of Cariri, Crato, Ceará, Brazil.
Microb Pathog. 2021 Jun;155:104894. doi: 10.1016/j.micpath.2021.104894. Epub 2021 Apr 21.
Staphylococcus aureus is responsible for a series of infections occurring in both human and animal hosts. S. aureus SA1199B is a strain resistant to hydrophilic fluoroquinolone due to overproduction of the NorA efflux pump that has been used as a microbial model to evaluate if a compound act as efflux pump inhibitor. Finding substances from natural or synthetic origin able to reverse resistance mechanisms like those of efflux pumps is a challenge. The use of Chalcones and their derivatives is of great chemical and pharmacological interest, as they present a simple structure and several pharmacological activities. This study aims to evaluate the antibacterial potential of 4 synthetic chalcones, as well as to evaluate their action in the modulation of Norfloxacin resistance against the strain SA1199B strain. Microdilution assays were performed for evaluation of the antimicrobial activity. For evaluation of the modulating effect on resistance to Norfloxacin or EtBr, MIC values of these compounds were determined in the absence or presence of subinhibitory concentrations used of each chalcone. MICs values of both Norfloxacin and EtBr were significantly reduced in the presence of all tested chalcones, indicating that inhibition of the active efflux of these compounds by NorA could be a possible mechanism of action of the chalcones. These results show that the compounds studied have a high potential as a NorA inhibitor, with the best modulating effect verified for the compound 3. Pharmacokinetic and toxicity predictive studies indicated a high intestinal absorption and good volume of distribution for chalcones by oral administration, activity in the central nervous system and ease to be transported between biological membranes. Emphasizing that analogs 1 and 4 were easily metabolized by CYP3A4 enzyme, constituting a pharmacological active ingredient without toxic risk due to metabolic activation. These chalcones combined with Norfloxacin could be a promise technological strategy to be applied in the treatment of infections caused by S. aureus overproducing NorA.
金黄色葡萄球菌可引发人类和动物宿主的一系列感染。金黄色葡萄球菌SA1199B菌株因过量表达NorA外排泵而对亲水性氟喹诺酮耐药，该菌株已被用作微生物模型来评估化合物是否可作为外排泵抑制剂。寻找能够逆转诸如外排泵等耐药机制的天然或合成来源物质是一项挑战。查耳酮及其衍生物因其结构简单且具有多种药理活性而具有极大的化学和药理学研究价值。本研究旨在评估4种合成查耳酮的抗菌潜力，并评估它们对诺氟沙星对SA1199B菌株耐药性的调节作用。采用微量稀释法评估抗菌活性。为评估对诺氟沙星或溴化乙锭耐药性的调节作用，在不存在或存在各查耳酮亚抑菌浓度的情况下测定这些化合物的最低抑菌浓度（MIC）值。在所有测试的查耳酮存在下，诺氟沙星和溴化乙锭的MIC值均显著降低，表明查耳酮可能通过抑制NorA对这些化合物的主动外排发挥作用。这些结果表明，所研究的化合物作为NorA抑制剂具有很高的潜力，其中化合物3的调节效果最佳。药代动力学和毒性预测研究表明，查耳酮口服给药时肠道吸收高、分布容积良好，在中枢神经系统有活性且易于在生物膜间转运。需要强调的是，类似物1和4易被CYP3A4酶代谢，因代谢激活而不构成有毒风险的药理活性成分。这些查耳酮与诺氟沙星联合使用可能是一种有前景的技术策略，可用于治疗由过量表达NorA的金黄色葡萄球菌引起的感染。
