Tuberculosis, an ancient infectious disease caused by Mycobacterium tuberculosis, ranks as
one of the top ten killers worldwide. The limited number of validated targets and scarce therapeutic options
demand that renewed efforts should be made to identify tuberculosis drugs with novel mechanisms
of action. To this end, mycobacterial DNA might represent a potential target for the development of effective
anti-tubercular compounds. In particular, the minor groove of DNA offers an important recognition
site for small-molecules that can be programmed to bind to this region in a sequence-selective
manner to disrupt mycobacterial transcription factors activity and ultimately cause bacterial cell death.
This review describes the structural features of the DNA-minor groove, the requirements for small
molecules to bind to this site and the remarkable biophysical and antibacterial properties of DNA-minor
groove binding agents, including netropsin, distamycin and their poly-heterocyclic analogues, diamidines,
benzimidazole-containing molecules, duocarmycins and pyrrolo[2,1-c][1,4]benzodiazepines
(PBDs). Furthermore, the ability of selected heterocyclic-polyamides and PBDs to significantly inhibit
the growth of pathogenic, slow-growing M. tuberculosis and other non-pathogenic mycobacterial strains
is highlighted. In summary, DNA-minor groove binding agents may serve as molecular scaffolds for the
design of highly efficient probes to treat M. tuberculosis infections.