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Combination of bactericidal antibiotics and inhibitors of Universal stress protein A (UspA): a potential therapeutic alternative against multidrug resistant Escherichia coli in urinary tract infections
The Journal of Antibiotics ( IF 2.1 ) Pub Date : 2021-09-15 , DOI: 10.1038/s41429-021-00477-4
Debojyoty Bandyopadhyay 1 , Mandira Mukherjee 1
Affiliation  

The increasing incidence of multidrug resistant uropathogenic E. coli (MDR-UPEC), the most common opportunistic pathogen in urinary tract infections (UTI) pose a global health problem and demands searching for alternative therapeutics. Antibiotics generate oxidative stress in bacteria which results in overexpression of the universal stress protein, UspA that helps in bacterial survival. An in silico study showed that two compounds ZINC000104153710, and ZINC000000217308 effectively bound bacterial UspA. This study aimed to determine the activity of ZINC000104153710, and ZINC000000217308 against bacterial UspA function in MDR-UPEC in vitro. Twenty-five highly MDR-UPEC were screened against ZINC000104153710, and, ZINC000000217308 either alone or in combination with the bactericidal antibiotics; ciprofloxacin (CIP), ceftazidime(CAZ), gentamicin(GEN) respectively by determining minimum inhibitory concentrations (MICs) using a broth microdilution assay. Additionally, the effect of ZINC000104153710, and ZINC000000217308 in the absence and presence of antibiotics on the bacteria was monitored by bacterial growth curve assays, ROS production, structure of the organism by scanning electron microscopy (FESEM) and quantitating UspA using a western blot technique. A 2–8 fold reduction in MIC values against ZINC000104153710, and ZINC000000217308 was observed against all 25 MDR-UPEC isolates in the presence of antibiotics with no alteration in intracellular ROS production. Discrete changes in cell morphology was evident in bacteria treated with ZINC000104153710 or ZINC000000217308 and antibiotics individually by FESEM compared with untreated control. Reduction in the level of UspA protein in bacteria treated with combination of ZINC000104153710 or ZINC000000217308 with individual antibiotics established their ability to inhibit UspA whose expression was elevated in presence of antibiotics alone. Therefore this study validated ZINC000104153710, and ZINC000000217308 as potent inhibitors of bacterial UspA function and indicated their potential as alternative therapeutics to combat the MDR-UPEC.



中文翻译:

杀菌抗生素和通用应激蛋白 A (UspA) 抑制剂的组合:一种针对尿路感染中多重耐药大肠杆菌的潜在治疗替代品

多药耐药性尿道致病性大肠杆菌的发病率不断增加(MDR-UPEC) 是尿路感染 (UTI) 中最常见的机会性病原体,它构成了一个全球性的健康问题,需要寻找替代疗法。抗生素在细菌中产生氧化应激,导致通用应激蛋白 UspA 过度表达,帮助细菌存活。一项计算机研究表明,两种化合物 ZINC000104153710 和 ZINC000000217308 可有效结合细菌 UspA。本研究旨在确定 ZINC000104153710 和 ZINC000000217308 在体外对 MDR-UPEC 中细菌 UspA 功能的活性。针对 ZINC000104153710 和 ZINC000000217308 单独或与杀菌抗生素联合筛选了 25 个高度 MDR-UPEC;环丙沙星 (CIP)、头孢他啶 (CAZ)、庆大霉素 (GEN) 分别通过使用肉汤微量稀释法确定最小抑菌浓度 (MIC)。此外,ZINC000104153710 和 ZINC000000217308 在不存在和存在抗生素的情况下对细菌的影响通过细菌生长曲线测定、ROS 产生、通过扫描电子显微镜 (FESEM) 的生物体结构和使用蛋白质印迹技术定量 UspA 来监测。在抗生素存在的情况下,观察到针对 ZINC000104153710 和 ZINC000000217308 的 MIC 值降低 2-8 倍,而细胞内 ROS 的产生没有变化。与未处理的对照相比,用 FESEM 分别用 ZINC000104153710 或 ZINC000000217308 和抗生素处理的细菌的细胞形态的离散变化是明显的。ZINC000104153710 或 ZINC000000217308 与单独抗生素的组合处理的细菌中 UspA 蛋白水平的降低确定了它们抑制 UspA 的能力,UspA 的表达在抗生素单独存在时升高。因此,本研究验证了 ZINC000104153710 和 ZINC000000217308 作为细菌 UspA 功能的有效抑制剂,并表明它们作为替代疗法对抗 MDR-UPEC 的潜力。

更新日期:2021-09-15
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