Synthesis and in Vitro Characterization of Trehalose‐Based Inhibitors of Mycobacterial Trehalose 6‐Phosphate Phosphatases

Abstract

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 [IC50=(288±32) μm] acting most strongly, followed by TNP [IC50=(421±24) μm] and TEP [IC50=(1959±261) μm]. The results also indicate significant differences in the analogue binding profile when comparing Mtb TPP, Mlt TPP, and Mtx TPP homologues.

Trehalose and bacterial virulence

“…Recently, there has been some exciting work to devise inhibitors specific for OtsB of Mycobacteria which are based on substrate analogs. These results showed that 6- N -phosphonamide 6 (TNP) exhibited the highest inhibitory activity toward the M. tuberculosis OtsB [ 77 ].…”

Structural basis of trehalose recycling by the ABC transporter LpqY-SugABC

“…Trehalose (-d-glucopyranosyl--d-glucopyranoside) is an essential nonreducing disaccharide used in bacteria, fungi, parasitic nematodes, insects, and plants, but it is not used in vertebrates (1)(2)(3)(4)(5). It has several functions including as a source of carbon and energy, as a signaling molecule to control metabolic pathways, and also to protect cellular membranes and proteins from denaturation or inactivation caused by a variety of stress conditions including desiccation, heat, dehydration, cold, and oxidation (3,5,6).…”

Synthetic Approaches to Phosphasugars (2-oxo-1,2-oxaphosphacyclanes) Using the Anomeric Alkoxyl Radical β-Fragmentation Reaction as the Key Step

“…4f As one might expect this correlation of the 2 J PH2 with phosphorus stereochemistry does not seem to be applicable to our 2deoxy compounds, in which the 2 J PH2 and 2 J PH2 are in general very similar and considerably higher (ca. [16][17][18][19][20].…”