Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan.
Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan; Center of Biotechnology and Microbiology, University of Peshawar, Pakistan; Department of Microbiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
Microb Pathog. 2020 Sep;146:104245. doi: 10.1016/j.micpath.2020.104245. Epub 2020 May 11.
The emergence of carbapenem-resistant Klebsiella Pneumoniae had been reported previously, which needs rapid attention. Currently, Pittsburgh University Hospital reported a new strain of carbapenem-resistant Klebsiella pneumoniae that was co-producing OXA-232 and NDM-1 named as PittNDM01. This strain is resistant to almost all beta-lactam antibiotics such as Carbapenem as well as to fluoroquinolones and aminoglycosides. Globally, failure to the wide-spread pathogenic strains had been observed due to the increased and antibiotic resistance, which leads to less antimicrobial drug efficacy. Since last decades, computational genomic approaches have been introduced to fight against resistant pathogens, which is an advanced approach for novel drug targets investigation. The current study emphasizes the utilization of the available genomic and proteomic data of Klebsiella pneumoniae PittNDM01 for the identification of novel drug targets for future drug developments. Comparative genomic analysis and molecular biological tools were applied, results in observing 582 non-human homologous-essential proteins of Klebsiella pneumoniae. Among the total 582 proteins, 66 were closely related to the pathogen-specific pathway. Out of all 66-targeted proteins, ten non-homologous essential proteins were found to have druggability potential. The subcellular localization of these proteins revealed; 6 proteins in the cytoplasm, 2 in the inner membrane, and one each in periplasmic space and outer membrane. All the above 10 proteins were compared to the proteins sequences of gut flora to eliminate the homologous proteins. In total, 6-novel non-human and non-gut flora essential drug targets of Klebsiella pneumoniae PittNDM01 strain were identified. Further, the 3D structures of the identified drug target proteins were developed, and protein-protein interaction network analysis was performed to know the functional annotation of the desire proteins. Therefore, these non-homologous essential targets ensure the survival of the pathogen and hence can be targeted for drug discovery.
先前已有报道称，碳青霉烯类耐药肺炎克雷伯菌已经出现，这需要引起高度关注。目前，匹兹堡大学医院报告了一种新的产碳青霉烯酶肺炎克雷伯菌，其同时产生 OXA-232 和 NDM-1，被命名为 PittNDM01。该菌株对几乎所有β-内酰胺类抗生素（如碳青霉烯类）以及氟喹诺酮类和氨基糖苷类抗生素均具有耐药性。由于广泛传播的致病性菌株出现了耐药性的增加，导致抗菌药物疗效降低，全球范围内已经观察到治疗失败的情况。几十年来，计算基因组方法已被引入以对抗耐药病原体，这是一种针对新型药物靶点研究的先进方法。本研究强调利用现有的肺炎克雷伯菌 PittNDM01 基因组和蛋白质组数据，确定用于未来药物开发的新型药物靶点。应用比较基因组分析和分子生物学工具，观察到肺炎克雷伯菌的 582 个非人类同源必需蛋白。在总共 582 种蛋白质中，有 66 种与病原体特异性途径密切相关。在所有 66 个靶向蛋白中，发现有 10 个非同源必需蛋白具有成药性潜力。这些蛋白的亚细胞定位显示；6 种蛋白位于细胞质中，2 种位于内膜中，1 种分别位于周质空间和外膜中。将上述所有 10 种蛋白与肠道菌群的蛋白序列进行比较，以消除同源蛋白。总共鉴定出 6 种新型非人类和非肠道菌群的肺炎克雷伯菌 PittNDM01 必需药物靶点。进一步开发了鉴定出的药物靶蛋白的 3D 结构，并进行了蛋白质-蛋白质相互作用网络分析，以了解所需蛋白质的功能注释。因此，这些非同源必需靶标确保了病原体的存活，因此可以作为药物发现的靶点。
