Tuberculosis remains the world’s deadliest communicable bacterial disease with an unacceptably high death rate. In 2013 an estimated 1.5 million people died as a direct result of TB, and nine million new cases were reported. Multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis cases are on the rise and without novel approaches to combat their spread, tuberculosis will continue to claim the lives of millions worldwide. One such novel approach is to rejuvenate the use of the second-line antibiotic ethionamide. Ethionamide is a structural analogue of the first-line pro-drug isoniazid, which is used widely and to which there is growing resistance. Ethionamide was introduced in the 1960s and primarily used in cases of drug-resistant TB due to its severe adverse effects. This makes ethionamide an exploitable target for small-molecule booster drugs. Expression of the enzyme responsible for ethionamide activation, EthA, is regulated by a transcriptional repressor EthR which can be inhibited to improve ethionamide activation and so reduce ethionamide treatment doses and bring an old drug new life in the clinic. EthR inhibitors are currently in development; here, chemoinformatic pipelining and virtual screening in GOLD were used to identify hits with novel scaffolds for hit-to-lead efforts from an initial library of over six million drug-like molecules. Thermal shift assays were used to identify EthR-binding molecules and SPR was utilised to confirm and potentially quantify binding affinities. Herein are reported the co-crystal structures of several hit molecules, used to confirm and characterise the EthR-ligand complexes. Through the application of computational, biophysical and crystallographic methods, this thesis presents several novel scaffolds for development against EthR. These novel hits will be developed to expand our arsenal against the growing, global problem of drug-resistant TB.