Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). One third of the world’s population is infected with TB resulting in 1.7 million deaths each year. The current arsenal of antibiotics to treat this bacterial infection is losing efficacy due to drug resistance. This is highlighted by the emergence of new strains of M. tuberculosis (TDR) in India that are resistant to all first and second line antibiotics. New antibiotic classes that are not subject to current resistance mechanisms are desperately required. One novel approach to anti-TB discovery is to identify small molecules that target the utilisation of biotin. Biotin is an important enzyme cofactor that is post-translationally attached to specific biotin-dependent enzymes by biotin protein ligase (BPL) [1,2]. Due to the essential metabolic role played by BPL in M. tuberculosis, this enzyme is a promising new anti-TB drug target. As humans also possess BPL the discovery of inhibitors that are selective for the bacterial pathogen, but not the human equivalent, is an important consideration. Our team has discovered a new class of antibiotic, the biotin triazoles, that are chemical analogues of the adenylated reaction intermediate naturally employed by BPLs. Enzyme assays have shown that the biotin triazoles inhibit MtBPL but not the human equivalent, thereby providing a therapeutic window for selective BPL inhibitors. A series of analogues based upon the biotin triazole pharmacophore have been synthesised and tested yielding a structure – activity relationship (SAR) series. The data from this SAR series has identified new chemical structures with further potential in antibiotic discovery. Our goal is to now design and chemically optimise of next generation biotin triazoles with potential for combating drug resistant TB.

1. Salaemae. W., Azhar, A., Booker, G.W., Polyak, S.W,  Protein & Cell, 2011. 2(9): p. 5.
2. Duckworth, Benjamin P., et al.,  Chemistry & Biology, 2011. 18(11): p. 1432-1441.