A Fragment-based Approach to Assess the Ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine Biosynthetic Pathway of

The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against . These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes.