Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan-23200, Pakistan.
Department of Biochemistry, Bahauddin Zakariya University, Multan-66000, Pakistan.
Mini Rev Med Chem. 2021;21(18):2778-2787. doi: 10.2174/1389557520666200707133347.
Brucella melitensis is a facultative intracellular bacterial pathogen that causes abortion in goats and sheep and Malta fever in humans. In humans, chronic infection occurs through contact with infected animals or their waste products.
The subtractive genomic approach is considered as a powerful and useful method for the identification of potential drug and vaccine targets. In this study, an attempt has been made through a subtractive proteomic strategy to identify novel drug targets in Brucella melitensis strains. Total 2604 core proteins of 56 strains of B. melitensis were taken, of which 545 non-human homologs were found to be essential for pathogen growth. Metabolic pathway analysis of these essential proteins revealed that 129 proteins are exclusively involved in 21 unique metabolic pathways in B. melitensis reference strain.
Of these, 31 proteins were found to be involved in 10 metabolic pathways that are unique to the pathogen. We selected Nitrate reductase subunit-β, Urease subunit α-2, Pantoate-β-alanine ligase, Isochorismatase, 2-dehydro-3-deoxyphosphooctonate aldolase and Serine O-acetyltransferase as drug targets in Brucella melitensis strains. Among these druggable targets, we selected only Pantoate-β- alanine ligase as high confidence target based on intensive literature curation, which is nonhomologous to the human gut metagenome involved in biosynthesis of secondary metabolites pathway. Pantothenate synthetase is the best chemotherapeutic target to combat Brucellulosis.
Furthermore, in vitro and in vivo validation is needed for the evaluation of lead compounds against Brucella melitensis strains.
贝氏疏螺旋体是一种兼性细胞内细菌病原体，可导致山羊和绵羊流产以及人类马耳他热。在人类中，慢性感染是通过接触受感染的动物或其排泄物而发生的。
消减基因组方法被认为是鉴定潜在药物和疫苗靶点的有力且有用的方法。在这项研究中，我们试图通过消减蛋白质组学策略来鉴定贝氏疏螺旋体菌株中的新药物靶点。共选取了 56 株贝氏疏螺旋体的 2604 个核心蛋白，其中发现 545 个非人类同源物对病原体生长是必需的。对这些必需蛋白的代谢途径分析表明，129 个蛋白仅参与贝氏疏螺旋体参考株的 21 个独特代谢途径。
其中，有 31 个蛋白被发现参与了 10 个仅存在于病原体中的代谢途径。我们选择硝酸盐还原酶亚基-β、脲酶亚基α-2、泛酸-β-丙氨酸连接酶、异邻苯二酮酶、2-去氢-3-脱氧磷辛醛缩酶和丝氨酸 O-乙酰转移酶作为贝氏疏螺旋体菌株的药物靶点。在这些可成药的靶点中，我们仅根据密集的文献整理选择泛酸-β-丙氨酸连接酶作为高可信度靶点，该靶点与参与次生代谢物途径生物合成的人类肠道宏基因组没有同源性。泛酸合酶是治疗布鲁氏菌病的最佳化学治疗靶点。
此外，需要对针对贝氏疏螺旋体菌株的先导化合物进行体外和体内验证。
