Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis (Mtb) the etiological agent of TB and is one of the top 10 causes of death worldwide. Many drugs have been developed to treat TB; however, the disease remains difficult to treat and drug resistance to approved drugs is growing. Most drugs target the biosynthesis of the cell wall because it is vital for the viability of Mtb and it also blocks drugs from entering the cell. Trehalose is an essential metabolite in Mtb that plays the role of transfer of mycolic acid in the form of trehalose monomycolate (TMM) to generate the mycolyl-arabinogalactan (mAG) and trehalose dimycolate (TDM) which are major constituents of the outer membrane. There are three biosynthetic pathways for the production of trehalose out of which Ots A/B or TPS-TPP2 is the major pathway. Trehalose Phosphate Phosphatase 2 (TPP2) is essential for the production of trehalose as it dephosphorylates trehalose-6-phosphate (T6P) to generate trehalose which is further utilized by other enzymes. It is anticipated that the accumulation of T6P will be lethal to the cell as reported by Farelli et al. Therefore, to inhibit TPP2 we synthesized one carbon phosphonate and two carbon phosphonate trehalose substrate analog of T6P. One carbon phosphonate was synthesized by a Michaelis-Arbuzov reaction by treating a 6-iodotrehalose derivative with trimethyl phosphite. A two carbon phosphonate was synthesized by Horner Wadsworth Emmons reactions by reacting corresponding the aldehyde with tetramethyl methylene diphosphonate. The TPP2 enzyme has an aspartate residue in its active site which acts as a nucleophile, similar approach is seen in soluble Epoxide Hydrolase (she) therefore, we propose an epoxide as a suicide substrate which will form an alkylenzyme ester intermediate irreversibly. Ongoing studies of these substrate analogs with TPP2 enzyme will inform the design of new inhibitors of TPP2.

Synthesis and inhibition studies of substrate and suicide analogs for Mycobacterium tuberculosis for trehalose phosphate phosphatase (TPP2)

254th National Meeting (2017)

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