In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

摘要: Existing macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved macrolide resistance Mycobacterium tuberculosis, a mechanism newer been designed to overcome gram-positive bacteria. Therefore, selected and ketolides (descladinose) with substitutions at positions 9, 11,12, 6 were assessed for activity against M. those MICs of ≤4 μM evaluated cytotoxicity Vero cells J774A.1 macrophages. Several compounds 9-oxime or aryl position on 11,12 carbamates carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, superior activity. Four low also effected significant reductions CFU infected Active tolerance ability reduce lungs BALB/c mice an aerosol infection model. A substituted carbazate dose-dependent inhibition tuberculosis growth mice, 10- 20-fold reduction lung tissue. Structure-activity relationships, some which are unique several synthetic directions further improvement antituberculosis This class appears promising yielding clinically useful agent