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

• Published in: Antimicrobial agents and chemotherapy Vol. 43; no. 3; pp. 661 - 666
• Main Authors: BEN YANG ZHAO, PINE, R, DOMAGALA, J, DRLICA, K
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.03.1999
• Subjects: Anti-Infective Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Cell Line; Ciprofloxacin - analogs & derivatives; Ciprofloxacin - pharmacology; Culture Media; DNA Gyrase; DNA Topoisomerases, Type II - genetics; DNA Topoisomerases, Type II - metabolism; Humans; In Vitro Techniques; Macrophages - drug effects; Macrophages - microbiology; Mechanisms of Action: Physiological Effects; Medical sciences; Mutation; Mycobacterium bovis - drug effects; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - isolation & purification; Pharmacology. Drug treatments; Structure-Activity Relationship; Human; Culture medium; Microorganism growth; Liquid medium; In vitro; Biological activity; Fluoroquinolone derivatives; Mycobacterium tuberculosis; Structure activity relation; Mycobacteriales; Mycobacteriaceae; Bacteria; Actinomycetes; Mutation; Antibacterial agent; Macrophage
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.43.3.661

When the lethal action of a C-8 methoxyl fluoroquinolone against clinical isolates of Mycobacterium tuberculosis in liquid medium was measured, the compound 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 ciprofloxacin against cells having a wild-type gyrA (gyrase) gene. Against ciprofloxacin-resistant strains, the C-8 methoxyl group enhanced lethality when 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 infection 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 same concentration of a C-8-H fluoroquinolone. The C-8 methoxyl fluoroquinolone 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 group 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 antituberculosis agents.