Abstract
The purpose of this study is to investigate the effectiveness of a new substance, LK1676, from the series of nitroheterocyclic compounds, which has in vitro antituberculosis activity against drug-sensitive (DS) and drug-resistant (DR) Mycobacterium tuberculosis strains, in the context of monotherapy for experimental tuberculosis infection. C57BL/6 mice were inoculated into the tail vein with a suspension of LK1676, an international virulent test strain of M. tuberculosis H37Rv, or a clinical strain of M. tuberculosis of the Beijing genotype with multiple drug resistance (MDR). LK1676 was administered for 6 weeks as a monotherapy per os at a dose of 10 mg/kg, while the comparison drugs were pyrazinamide (Z) ethambutol (E), moxifloxacin (Mfx), and linezolid (Lzd) at therapeutic doses. The effectiveness of the therapy was evaluated using biometric, bacteriological, and histological methods. Monotherapy of LK1676 mice infected with the HPV strain M. tuberculosis H37Rv reduced the bacterial load in the lungs (p<0.03), biometric parameters of the lungs (p<0.005) and spleen (p<0.007), the prevalence of specific lesions in lung tissue, the disappearance of signs of destruction, increased local lung immunity in terms of severity of perivascular and peribronchial infiltration, as well as the cellular composition of the inducible bronchoassociated lymphoid tissue (iBALT). The efficacy of LK1676 was comparable to that of Mfx and Z, but significantly lower than that of E. Monotherapy with LK1676 for MDR TB led to a significant reduction in the clearance of M. tuberculosis from the lungs, the lung mass coefficient, and the index of their lesion, which corresponded to the level of effect of Mfx, but less pronounced than that of E and Lzd. The results obtained indicate that the compound 1-[(5-nitrofuran-2-yl)carbonyl]-2’-cyclohexyl-1h,7’h-spiro[azetidin-3,5’-furo[3,4-d]pyrimidine] with the laboratory code LK1676 is promising for further study.