Abstract

The global increase in the morbidity/mortality rate of Mycobacterial infections, predominantly renascent tuberculosis, leprosy, and Buruli ulcers have become worrisome over the years. More challenging is the incidence of resistance mediated by mutant Mycobacterium strains against front-line antitubercular drugs. Homologous to all Mycobacteria species is the GlcNAc-6-phosphate deacetylase (NagA) which catalyzes essential amino sugars synthesis required for cell wall architecture, hence, metamorphosing into an important pharmacological target for curtailing virulence and drug-resistance. This study used integrated bioinformatics methods, MD simulations, and DynaMut and PolyPhen2 to; explore unique features, monitor dynamics, and analyze the functional impact of non-synonymous single-nucleotide polymorphisms of the six NagA of most ruinous Mycobacterium species; tuberculosis (Mtb), smegmatis (MS), marinum (MM), ulcerans, africanum, and microti respectively. This approach is essential for multi-targeting and could result in the identification of potential polypharmacological antitubercular compounds. Comparative sequential analyses revealed ≤ 50% of the overall structure, including the catalytic Asp267 and reactive Cys131, remained conserved. Interestingly, MS-NagA and MM-NagA possess unique hydrophobic isoleucine (Ile) residues at their active sites in contrast to leucine (Leu) found in other variants. More so, unique to the active sites of the NagA is a ‘subunit loop’ that covers the active site; probably crucial in binding (entry and exit) mechanisms of targeted NagA inhibitors. Relatively, nsSNP mutations exerted a destabilizing effect on the native NagA conformation. Structural and dynamical insights provided, basically pin-pointed the “Achilles’ heel” explorable for the rational drug design of target-specific ‘NagA’ inhibitors potent against a wide range of mycobacterial diseases.

Graphic Abstract

中文翻译：

---

深入研究“ Menace”结核分枝杆菌同系物的特征：结构动力学和蛋白质组学观点。

摘要

多年来，全球范围内分枝杆菌感染，主要是新生肺结核，麻风病和布鲁里溃疡的发病率/死亡率上升令人担忧。更具挑战性的是突变型分枝杆菌菌株介导的针对一线抗结核药物的耐药性发生率。与所有分枝杆菌物种同源的是GlcNAc-6-磷酸脱乙酰酶（NagA），它催化细胞壁结构所需的必需氨基糖合成，因此，变成了降低毒力和耐药性的重要药理靶标。这项研究使用了整合的生物信息学方法，MD模拟以及DynaMut和PolyPhen2至; 探索独特的特征，监测动态，并分析大多数毁灭性分枝杆菌物种的六个NagA的非同义单核苷酸多态性的功能影响；结核（Mtb），耻垢（MS），马林（MM），溃疡，非洲人和小肠菌。该方法对于多目标必不可少，并且可能导致鉴定潜在的多药理抗结核化合物。比较的顺序分析显示，≤50％的整体结构（包括催化性Asp267和反应性Cys131）保持保守。有趣的是，MS-与在其他变体中发现的亮氨酸（Leu）相反，NagA和MM- NagA在其活性位点具有独特的疏水异亮氨酸（Ile）残基。更重要的是，NagA活性位点所特有的是覆盖活性位点的“亚基环”。可能对靶向NagA抑制剂的结合（进入和退出）机制至关重要。相对而言，nsSNP突变对天然NagA构象产生不稳定作用。提供的结构和动力学见解基本上指出了“致命弱点”，可用于针对多种分支杆菌疾病有效的靶标特异性“ NagA”抑制剂的合理药物设计。

图形摘要