A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of <i>Mycobacterium tuberculosis</i>
Pooja Gupta, S.E. Thomas, Shaymaa A. Zaidan, Maria A. Pasillas, J. Cory-Wright, Víctor Sebastián-Pérez, Ailidh Burgess, Emma Cattermole, C. Meghir, Chris Abell, Anthony G. Coyne, William R. Jacobs, Tom L. Blundell, Sangeeta Tiwari, V. Mendes
Abstract
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 Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis 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 M. tuberculosis. These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes.