The secreted Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatase B (MptpB) is an essential virulence factor required for the intracellular survival of Mtb within host macrophages. MptpB has become a promising target for the development of novel anti-tuberculosis (TB) drugs. In this study, two new fusarielins, fusarielin M (1) and N (2), and a biogenetically related known compound, fusarielin G (3) were isolated from the marine-derived fungus Fusarium graminearum SYSU-MS5127. Their inhibitory effects on MptpB were evaluated. Among these compounds, fusarielin M substantially inhibited MptpB with a half-maximal inhibitory concentration (IC₅₀) of 1.05 ± 0.08 μM, and an inhibition constant (K_i) of 1.03 ± 0.39 μM. Surface plasmon resonance analysis was used to characterize the interaction between fusarielin M and MptpB in vitro. Fusarielin M also exhibited cellular activity in blocking MptpB-mediated Erk1/2 and p38 inactivation in macrophages. Importantly, fusarielin M (20μM) substantially reduced intracellular mycobacterial growth within macrophages, causing a 62% reduction in the bacterial burden. The binding mode of fusarielin M was further explored via molecular docking which suggested that fusarielin M binds to the active site of MptpB, forming a hydrogen bond with the side chain of Asp165; this is unique in the P-loop of MptpB compared to conventional human PTPs. The contact between fusarielin M and Asp165 in the catalytic loop provides a potential basis for inhibitor selectivity. Therefore, fusarielin M shows great potential as an anti-TB drug candidate.

分泌的结核分枝杆菌 (Mtb)蛋白酪氨酸磷酸酶 B (MptpB) 是宿主巨噬细胞内Mtb细胞内存活所需的重要毒力因子。MptpB 已成为开发新型抗结核 (TB) 药物的有希望的目标。在本研究中，从海洋源真菌禾谷镰刀菌SYSU-MS5127中分离出两种新的镰刀菌素，镰刀菌素 M ( 1 ) 和 N ( 2 )，以及一种生物遗传相关的已知化合物镰刀菌素 G ( 3 ) 。评估了它们对 MptpB 的抑制作用。在这些化合物中，镰刀菌素 M 以半数最大抑制浓度（IC ₅₀) 为 1.05 ± 0.08 μM，抑制常数 ( K _i ) 为 1.03 ± 0.39 μM。表面等离子体共振分析用于表征镰刀菌素 M 和 MptpB在体外的相互作用. Fusarielin M 在阻断巨噬细胞中 MptpB 介导的 Erk1/2 和 p38 失活方面也表现出细胞活性。重要的是，镰刀菌素 M (20μM) 显着减少了巨噬细胞内细胞内分枝杆菌的生长，使细菌负担减少了 62%。通过分子对接进一步探索了镰刀菌素M的结合模式，表明镰刀菌素M与MptpB的活性位点结合，与Asp165的侧链形成氢键；与传统的人类 PTP 相比，这在 MptpB 的 P 环中是独一无二的。催化环中镰刀菌素 M 和 Asp165 之间的接触为抑制剂选择性提供了潜在的基础。因此，镰刀菌素 M 作为抗结核候选药物显示出巨大的潜力。