BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB. The MIC of BTZ043 against M. tuberculosis H37Rv and Mycobacterium smegmatis were 1 ng/ml (2.3 nM) and 4 ng/ml (9.2 nM), respectively. BTZ043 displays similar activity against all clinical isolates of M. tuberculosis that were tested, including multidrug-resistant and extensively drug-resistant strains. BTZ043 is bactericidal, reducing viability in vitro by more than 1000-fold in under 72 hours, which is comparable to the killing effect seen with INH.[1] BTZ043 acts synergistically with TMC207, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng/ml) used in combination with BTZ043 (1/4 MIC, 0.375 ng/ml) had a stronger bactericidal effect on M. tuberculosis than TMC207 alone at a concentration of 80 ng/ml. The sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of TMC207 to its target.[2]
In vivo
In two different model systems (auxotrophy and starvation) involving metabolically inert M. tuberculosis, BTZ043 was less effective, which implies that it blocks a step in active metabolism, similar to INH.[1]