Abstract : The DNA binding protein HU plays an important role in maintenance of chromosomal architecture and in global regulation of DNA transactions in bacteria. Although HU is essential for growth of Mycobacterium tuberculosis ( Mtb ) there have been no reported attempts to perturb HU function with small molecules. We report the crystal structure of the N-terminal domain of HU from Mtb. We identify a core region within the HU-DNA interface that was targeted using stilbene derivatives. These small molecules specifically inhibit HU-DNA binding, disrupt nucleoid architecture and reduce Mtb growth. Our results indicate that HU is a potential target for the development of therapies against tuberculosis. ( Nature Communications, June 2014 )