Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis
复制标题
新型 Coumestan 衍生物作为结核分枝杆菌聚酮合酶 13 抑制剂的鉴定
DOI：
10.1021/acs.jmedchem.7b01319
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发表时间：
2018-02-08
影响因子：
7.3
通讯作者：
Yu, Li-Fang
中科院分区：
文献类型：
--
作者：
Zhang, Wei;Lung, Shichun;Yu, Li-Fang
抑制霉菌酸途径已被证明是一种可行的抗结核药物发现策略。结核分枝杆菌的AccA3/AccD4/FadD32/Pks13复合体构成了霉菌酸的重要生物合成机制。针对Pks13的硫酯酶结构域的小分子已经被报道，包括一个基于苯并呋喃的化合物，其x射线共晶结构最近才被解决。它最初在血清抑制滴定（SIT）试验中没有活性，这促使我们进一步探索其他结构相关的苯并呋喃，目的是提高它们的效力和生物利用度。在此，我们报告了围绕该支架的初步结构活性关系研究，强调了一种天然产物启发的环化策略，以形成在SIT中被证明具有活性的coumestan。对库美斯坦耐药突变体的全基因组深度测序证实了导致耐药表型的pks13基因的单核苷酸多态性，证明了该靶点在开发新的抗结核药物方面的可药性。
Inhibition of the mycolic acid pathway has proven, a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.