Tuberculosis (TB), is one of the leading causes of death worldwide claiming 1.5 million lives every year. Mycobacterium tuberculosis (Mtb) is the causative bacterial pathogen of TB,  which evolved over years to be able to adapt itself according to changing conditions inside the host cell. This ability of adaption is resulting in the emergence of drug-resistant strains. The cell envelope of Mtb acts as a shield against antibiotics. Cell envelope has inner and outer layers of membranes. The inner layer is primarily made of mycolyl arabinogalactan (mAG), whereas, the outer layer is made of glycolipids, phospholipids, sulpholipids, trehalose dimycolate (TDM), and trehalose monomycolate (TMM). Trehalose is an essential component of this complex cell wall. Trehalose act as a transporter of mycolic acid (MA) in the form of TMM from the cytoplasm to extracellular space for the synthesis of mAG, and TDM. This transferring process of MA is catalyzed by enzymes of the Antigen 85 complex. The enzymes of the Antigen 85 complex, three homologous transferases (Ag85A, Ag85B, Ag85C) play a vital role in the biosynthesis of cell wall complexity and survival of the pathogen. Starting from D-trehalose, the first step of the synthesis is a regioselective silylation of C-6 with tert-butyldiphenylsilyl chloride (TBDPSCl) in the presence of imidazole in DMF with 48%. The resulted compound will be subjected to the global benzylation with benzyl bromide and sodium hydride in DMF with a yield of 98%. Next, the silyl protective group is removed with tetrabutylammonium fluoride trihydrate (TBAF) in THF to produce benzylated trehalose with free alcohol at C-6 position with 96% yield. We incorporated different known esterase inhibitors i.e. lactone, and 1,1,1,3,3,3-hexafluoropropan-2-yl carbamate at C-6 position. Previously known trehalose derivatives were found to be active against Mtb H37Ra. We have evaluated these derivatives against Mtb H37Ra and M. smegmatis for growth inhibition. One of the synthesized derivatives with lactone moiety has shown the minimum inhibitory concentration (MIC) value of 100 µM against H37Ra. We have also performed a synergistic assay with 4-fold lower concentration than the MIC of lactone derivative in combination with 24 well-established TB/non-TB antibiotics. We have not observed any synergy between compound and antibiotics. We can derive that trehalose can be used as a carrier of antibacterial drug moieties to cross the complex barrier of the cell wall.

Synthesis and inhibition studies of trehalose analogs for the inhibition Ag85 complex in <i>mycobacterium</i> tuberculosis

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Synthesis and inhibition studies of trehalose analogs for the inhibition Ag85 complex in mycobacterium tuberculosis