Anti-Tb Efficacy Of Pbtz169 In Mice With Different Genetic Susceptibility To Infection

Backgound: The newly synthesized compound PBTZ169 is highly active against M. tuberculosis (Mtb) in vitro and in vivo (MIC=0.0001 ug/ml), and DprE1, an important Mtb cell wall biosynthesis enzyme, is its target. PBTZ169 is active against susceptible, MDR and XDR Mtb strains. Aims and Objectives: To study efficacy of PBTZ169 in inbred mice with different genetically determined susceptibility to tuberculosis infection. Methods: Mice of the I/St (H2j, susceptible) and C57BL/6 (H2b, resistant) inbred strains and recombinant H2-congenic strains B6.I-100 (H2-Aj, intermediate susceptibility) and B6.I-139 (H2-Ajb, intermediate resistance) were infected with virulent Mtb by aerosol. Treatment wth PBTZ169 (PO 50 mg/kg) was initiated 3 wk following challenge. Lung and spleen CFU were determined by plating serial dilutions of organ homogenates on agar. Lung tissue samples were fixed with acetone and stained with hematoxylin-eosin. Results: The efficacy of 2-mo therapy was higher for spleens of more susceptible I/St and B6.I-100 strains: log reduction compare to non-treated control for I/St mice were 2.52, for B6.I-100 - 2.46, for C57BL/6 - 1.93, for B6.I-139 - 1.54 (p=0.0095). Lung CFU log reduction appeared to be similar in all mouse strains. Conclusion: PBTZ169 demonstrates higher effect onto lung-to-spleen mycobacterial dissemination in TB-susceptible compare to TB-resistant mice.