(Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify , targeting PPM1A (IC = 1.19 μM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned to create , which is a more potent inhibitor for PPM1A (IC = 180 nM). efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. possesses a good pharmacokinetic profile and oral bioavailability ( = 74%). In vivo, is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.
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