Identification of Novel Mt-Guab2 Inhibitor Series Active against <em>M. tuberculosis</em>

Tuberculosis (TB) remains a leading cause of mortality worldwide. With the emergence of multidrug resistant TB, extensively drug resistant TB and HIV-associated TB it is imperative that new drug targets be identified. The potential of Mycobacterium tuberculosis inosine monophosphate dehydrogenase (IMPDH) as a novel drug target was explored in the present study. IMPDH exclusively catalyzes the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) in the presence of the cofactor nicotinamide adenine dinucleotide (NAD+). Although the enzyme is a dehydrogenase, the enzyme does not catalyze the reverse reaction i.e. the conversion of XMP to IMP. Unlike other bacteria, M. tuberculosis harbors three IMPDH-like genes, designated as Mt-guaB1, Mt-guaB2 and Mt-guaB3 respectively. Of the three putative IMPDH's, we previously confirmed that Mt-GuaB2 was the only functional ortholog by characterizing the enzyme kinetically. Using an in silico approach based on designed scaffolds, a series of novel classes of inhibitors was identified. The inhibitors possess good activity against M. tuberculosis with MIC values in the range of 0.4 to 11.4 µg mL−1. Among the identified ligands, two inhibitors have nanomolar Kis against the Mt-GuaB2 enzyme.结核病（Tuberculosis，简称TB）仍是全球范围内主要的致死性疾病之一。随着耐多药结核病、广泛耐药结核病以及HIV相关结核病的出现，识别新型药物靶点已成为当务之急。本研究探讨了结核分枝杆菌（Mycobacterium tuberculosis）肌苷单磷酸脱氢酶（inosine monophosphate dehydrogenase, IMPDH）作为新型药物靶点的潜力。在辅酶烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD+）存在的条件下，IMPDH可专一性催化肌苷单磷酸（inosine monophosphate, IMP）转化为黄苷单磷酸（xanthosine monophosphate, XMP）。尽管该酶属于脱氢酶类，但其无法催化逆反应，即无法将XMP转化为IMP。与其他细菌不同，结核分枝杆菌携带三个IMPDH同源基因，分别命名为Mt-guaB1、Mt-guaB2和Mt-guaB3。在这三个推定的IMPDH同源蛋白中，我们此前通过酶动力学表征，证实Mt-GuaB2是唯一具有功能的直系同源蛋白。本研究基于设计的骨架结构，采用计算机模拟（in silico）方法，识别出多类新型抑制剂。此类抑制剂对结核分枝杆菌具有良好的抗菌活性，其最低抑菌浓度（MIC）范围为0.4~11.4 μg·mL⁻¹。在此次识别得到的配体中，有两款抑制剂对Mt-GuaB2酶的抑制常数（Ki）达到纳摩尔级水平。