Naheed Shazia, Din Irum Umar, Qamar Muhammad Usman, Rasool Nasir, Ahmad Matloob, Bilal Muhammad, Khalid Aqsa, Ahmad Gulraiz, Al-Hussain Sami A, Zaki Magdi E A
Department of Chemistry, Government College University Faisalabad, Faisalabad, 38000, Pakistan.
Institute of Microbiology, Faculty of Life Sciences, Government College University, Faisalabad, 38000, Pakistan.
Infect Drug Resist. 2023 Aug 14;16:5295-5308. doi: 10.2147/IDR.S407891. eCollection 2023.
Global public health concerns include the emergence and spread of methicillin-resistant (MRSA) and extended-spectrum beta-lactamase (ESBL-). These pathogens cause infections that are difficult to treat, which can have fatal outcomes and require lengthy hospital stays. As a result, we created butyl 2-bromoisonicotinate and tested its antibacterial effectiveness against the ESBL- ST 405 and MRSA pathogens. Natural product discovery is complemented by synthetic compound synthesis because of the latter's potential for superior characteristics, target specificity, scalability, intellectual advantages, and chemical diversity. Because of this, the potential for discovering new medicinal compounds is increased, and the constraints placed on natural sources are overcome. Natural items are tough to obtain since they are hard to isolate and synthesize. Therefore, modern science is actively searching for small molecules as therapeutic agents by applying sustainable techniques that can be commercialized.
Two patients' blood samples were taken, and the BACTEC/Alert system was used to process them. On blood and MacConkey agar, the positive samples were subcultured and incubated aerobically at 37 °C. Using the VITEK 2 compact system, the isolates were subjected to isolate identification and MIC. MLST of the ESBL- was performed by PCR. Additionally, Fischer esterification was used to create butyl 2-bromoisonicotinate in excellent yields. A commercially available palladium catalyst was then used to arylate the compound, resulting in medium to good yields of arylated butyl 2-bromoisonicotinates. Using the agar well diffusion assay and the micro-broth dilution method, we assessed the in-vitro activities of the synthesized molecules (3, 5a-h) against clinically isolated ESBL- ST405, and MRSA. A molecular operating environment was used to carry out in silico validation of the synthesized compounds' binding to the active site and to evaluate the stability of their molecular interactions with the target 2Y2T protein.
MRSA and ESBL-producing were identified as the two clinical isolates. While MRSA was also resistant to beta-lactam drugs and least resistant to vancomycin, ESBL-producing belonged to ST405 and was resistant to cephalosporins and sensitive to carbapenems. Good yields of the desired compounds were produced by our effective and economical synthesis. By using a micro-broth dilution assay, the Molecules (3, 5a, and 5d) were most effective against both resistant strains. The Molecules (3, 5a, 5b, and 5d) also displayed good binding energies.
The butyl 2-bromoisonicotinate displayed antibacterial efficacy against ESBL-producing ST405 and MRSA strains. After the in-vivo trial, this substance might offer an alternative therapeutic option.
全球公共卫生问题包括耐甲氧西林金黄色葡萄球菌（MRSA）和超广谱β-内酰胺酶（ESBL-）的出现和传播。这些病原体引起的感染难以治疗，可能导致致命后果，并且需要长时间住院。因此，我们合成了2-溴异烟酸丁酯，并测试了其对ESBL-ST405和MRSA病原体的抗菌效果。由于合成化合物具有潜在的优越特性、靶点特异性、可扩展性、知识优势和化学多样性，因此天然产物发现与合成化合物合成相辅相成。因此，发现新药用化合物的潜力增加，并且克服了对天然来源的限制。天然产物难以获得，因为它们难以分离和合成。因此，现代科学正在积极应用可商业化的可持续技术寻找小分子作为治疗剂。
采集两名患者的血样，并使用BACTEC/Alert系统进行处理。在血琼脂和麦康凯琼脂上，将阳性样本进行传代培养，并在37℃有氧条件下孵育。使用VITEK 2 compact系统对分离株进行鉴定和最低抑菌浓度（MIC）测定。通过聚合酶链反应（PCR）对ESBL-进行多位点序列分型（MLST）。此外，采用费歇尔酯化反应以高产率合成2-溴异烟酸丁酯。然后使用市售钯催化剂对该化合物进行芳基化反应，得到中等至良好产率的芳基化2-溴异烟酸丁酯。使用琼脂孔扩散法和微量肉汤稀释法，评估合成分子（3、5a-h）对临床分离的ESBL-ST405和MRSA的体外活性。使用分子操作环境对合成化合物与活性位点的结合进行计算机模拟验证，并评估其与靶标2Y2T蛋白分子相互作用的稳定性。
鉴定出MRSA和产ESBL-为两种临床分离株。虽然MRSA对β-内酰胺类药物也耐药，对万古霉素耐药性最低，但产ESBL-属于ST405，对头孢菌素耐药，对碳青霉烯类敏感。我们有效且经济的合成方法得到了高产率的目标化合物。通过微量肉汤稀释试验，分子（3、5a和5d）对两种耐药菌株最有效。分子（3、5a、5b和5d）也显示出良好的结合能。
2-溴异烟酸丁酯对产ESBL-的ST405和MRSA菌株显示出抗菌效果。经过体内试验后，该物质可能提供一种替代治疗选择。
