Fluoroquinolone action against clinical isolates of Mycobacterium tuberculosis: Effects of a C-8 methoxyl group on survival in liquid media and in human macrophages

When the lethal action of a C-8 methoxyl fluoroqninolone against clinical i solates of Mycobacterium tuberculosis in liquid medium was measured, the co mpound was found to be three to four times more effective (as determined by measuring the 90% lethal dose) than a C-8-H control fluoroquinolone or cip rofloxacin against cells having a wild-type gyrA (gyrase) gene. Against cip rofloxacin-resistant strains, the C-8 methoxyl group enhanced lethality whe n alanine was replaced by valine at position 90 of the GyrA protein or when aspartic acid 94 was replaced by glycine, histidine, or tyrosine. During i nfection of a human macrophage model by wild-type Mycobacterium bovis BCG, the C-8 methoxyl group lowered survival 20- to 100-fold compared with the s ame concentration of a C-8-H fluoroquinolone. The C-8 methoxyl fluoroquinol one was also more effective than ciprofloxacin against a gyrA Asn94 mutant of M. bovis BCG. In an M. tuberculosis-macrophage system the C-8 methoxyl g roup improved fluoroquinolone action against both quinolone-susceptible and quinolone-resistant clinical isolates. Thus, a C-8 methoxyl group enhances the bactericidal activity of quinolones with N1-cyclopropyl substitutions; these data encourage further refinement of fluoroquinolones as antitubercu losis agents.