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Synthesis and in Vitro Characterization of Trehalose‐Based Inhibitors of Mycobacterial Trehalose 6‐Phosphate Phosphatases
Author(s) -
Kapil Sunayana,
Petit Cecile,
Drago Victoria N.,
Ronning Donald R.,
Sucheck Steven J.
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800551
Subject(s) - trehalose , biochemistry , phosphatase , mycobacterium , mycobacterium tuberculosis , in vitro , ic50 , enzyme , virulence , biosynthesis , biology , chemistry , bacteria , microbiology and biotechnology , tuberculosis , gene , medicine , genetics , pathology
α,α′‐Trehalose plays roles in the synthesis of several cell wall components involved in pathogenic mycobacteria virulence. Its absence in mammalian biochemistry makes trehalose‐related biochemical processes potential targets for chemotherapy. The trehalose 6‐phosphate synthase (TPS)/trehalose 6‐phosphate phosphatase (TPP) pathway, also known as the OtsA/OtsB2 pathway, is the major pathway involved in the production of trehalose in Mycobacterium tuberculosis ( Mtb ). In addition, TPP is essential for Mtb survival. We describe the synthesis of α,α′‐trehalose derivatives in the forms of the 6‐phosphonic acid 4 (TMP), the 6‐methylenephosphonic acid 5 (TEP), and the 6‐ N ‐phosphonamide 6 (TNP). These non‐hydrolyzable substrate analogues of TPP were examined as inhibitors of Mtb , Mycobacterium lentiflavum ( Mlt ), and Mycobacterium triplex ( Mtx ) TPP. In all cases the compounds were most effective in inhibiting Mtx TPP, with TMP [IC 50 =(288±32) μ m ] acting most strongly, followed by TNP [IC 50 =(421±24) μ m ] and TEP [IC 50 =(1959±261) μ m ]. The results also indicate significant differences in the analogue binding profile when comparing Mtb TPP, Mlt TPP, and Mtx TPP homologues.