Mycobacterium Tuberculosis Lysine-Ɛ-Aminotransferase A Potential Target In Dormancy: Benzothiazole Based Inhibitors

MTB lysine-ɛ-aminotransferase (LAT) was found to play a crucial role in persistence and antibiotic tolerance. LAT serves as a potential target in the management of latent tuberculosis. In present work we attempted to derivatize the benzothiazole lead identified through high throughput virtual screening of Birla Institute of Technology and Science in house database. For Structure activity relationship purpose 22 derivatives were synthesized and characterized. Among synthesized compounds, eight compounds were found to be more efficacious in terms of LAT inhibition when compared to lead compound (IC50 10.38 ± 1.21 µM). Compound 22 exhibits bactericidal action against nutrient starved Mycobacterium tuberculosis (MTB). It also exhibits significant activity in nutrient starvation model (2.9 log folds) and biofilm model (2.3 log folds)

Structure-Guided Design of Novel Thiazolidine Inhibitors of <i>O</i>‑Acetyl Serine Sulfhydrylase from Mycobacterium tuberculosis

The cysteine biosynthetic pathway is absent in humans but essential in microbial pathogens, suggesting that it provides potential targets for the development of novel antibacterial compounds. CysK1 is a pyridoxalphosphate-dependent <i>O</i>-acetyl sulfhydrylase, which catalyzes the formation of l-cysteine from <i>O</i>-acetyl serine and hydrogen sulfide. Here we report nanomolar thiazolidine inhibitors of Mycobacterium tuberculosis CysK1 developed by rational inhibitor design. The thiazolidine compounds were discovered using the crystal structure of a CysK1–peptide inhibitor complex as template. Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound <b>2</b> (IC₅₀ of 103.8 nM), which was subsequently optimized by a combination of protein crystallography, modeling, and synthetic chemistry. Hit expansion of <b>2</b> by chemical synthesis led to improved thiazolidine inhibitors with an IC₅₀ value of 19 nM for the best compound, a 150-fold higher potency than the natural peptide inhibitor (IC₅₀ 2.9 μM)