Metal-dependent protein phosphatases (PPMs) have essential roles in a variety of cellular processes, including inflammation, proliferation, differentiation, and stress responses, which are intensively investigated in cancer and metabolic diseases. Targeting PPMs to modulate host immunity in response to pathogens is an ambitious proposition. The feasibility of such a strategy is unproven because development of inhibitors against PPMs is challenging and suffers from poor selectivity. Combining a biomimetic modularization strategy with function-oriented synthesis, we design, synthesize and screen more than 500 pseudo-natural products, resulting in the discovery of a potent, selective, and non-cytotoxic small molecule inhibitor for PPM1A, SMIP-30. Inhibition of PPM1A with SMIP-30 or its genetic ablation (ΔPPM1A) activated autophagy through a mechanism dependent on phosphorylation of p62-SQSTM1, which restricted the intracellular survival of Mycobacterium tuberculosis in macrophages and in the lungs of infected mice. SMIP-30 provides proof of concept that PPMs are druggable and promising targets for the development of host-directed therapies against tuberculosis.

金属依赖性蛋白磷酸酶 (PPM) 在多种细胞过程中发挥着重要作用，包括炎症、增殖、分化和应激反应，这些在癌症和代谢疾病中得到了深入研究。针对 PPM 调节宿主对病原体的免疫力是一个雄心勃勃的提议。这种策略的可行性尚未得到证实，因为针对 PPM 的抑制剂的开发具有挑战性并且选择性差。我们将仿生模块化策略与面向功能的合成相结合，设计、合成和筛选了 500 多种假天然产物，从而发现了一种有效的、选择性的、无细胞毒性的 PPM1A 小分子抑制剂 SMIP-30。巨噬细胞和受感染小鼠肺中的结核分枝杆菌。SMIP-30 提供了概念证明，即 PPM 是开发针对结核病的宿主导向疗法的可成药和有希望的目标。