Mechanistic perspective on regulation of Mycobacterium pathogenesis

Inorganic polyphosphate (polyP) serves as a crucial regulator in Mycobacterium tuberculosis, orchestrating a multitude of cellular processes pivotal for its survival and virulence. Polyphosphate Kinase-1 (PPK-1), polyP governs energy metabolism, stress response, and lipid biosynthesis, among other essential pathways. Recent findings from the Translational Health Science and Technology Institute (THSTI) shed light on the profound impact of polyP dysregulation on M. tuberculosis pathogenesis.
Deletion of ppk-1 results in a cascade of events, leading to transcriptional and metabolic reprogramming within the bacterium. The absence of polyP significantly diminishes the production of virulence-associated lipids, compromising the pathogen's ability to thrive in host tissues. Furthermore, polyP deficiency correlates with heightened phagosome–lysosome fusion in macrophages, ultimately impeding bacterial proliferation. Host transcriptomic analysis unveils the interplay between polyP and host immune responses. Mice infected with Δppk-1 mutant strains exhibit altered expression profiles of genes associated with type I interferon signaling and the formation of foamy macrophages, pivotal in tuberculosis pathogenesis.
Targeted screening and molecular docking efforts have led to the identification of raloxifene hydrochloride as a potent PPK-1 inhibitor. Raloxifene hydrochloride not only enhances the efficacy of frontline tuberculosis drugs such as isoniazid, bedaquiline, and pretomanid within macrophages but also demonstrates inhibitory effects on M. tuberculosis growth in murine models.This study elucidates the intricate regulatory role of polyP in mycobacterial pathogenesis and unveils raloxifene hydrochloride as a promising therapeutic adjunct in tuberculosis treatment. By targeting polyP regulation, novel therapeutic strategies have been suggested, potentially revolutionizing the landscape of tuberculosis management.