Targeting tuberculosis using structure-guided fragment-based drug design

•Despite worldwide efforts to treat the disease, TB continues to be a global threat.•HTS campaigns against TB have had a lower-than-expected rate of success.•Fragment-based approaches have been able to produce active leads against TB.•The merits of fragment-based drug discovery are discussed in the context of TB. Fragment-based drug discovery is now widely used in academia and industry to obtain small molecule inhibitors for a given target and is established for many fields of research including antimicrobials and oncology. Many molecules derived from fragment-based approaches are already in clinical trials and two – vemurafenib and venetoclax – are on the market, but the approach has been used sparsely in the tuberculosis field. Here, we describe the progress of our group and others, and examine the most recent successes and challenges in developing compounds with antimycobacterial activity.