title: Identification of (+)-erythro-mefloquine as an active enantiomer with greater efficacy than mefloquine against Mycobacterium avium infection in mice.
abstract: Infection caused by Mycobacterium avium is common in AIDS patients who do not receive treatment with highly active antiretroviral therapy (HAART) or who develop resistance to anti-HIV therapy. Mefloquine, a racemic mixture used for malaria prophylaxis and treatment, is bactericidal against M. avium in mice. MICs of (+)-erythro-, (-)-erythro-, (+)-threo-, and (-)-threo-mefloquine were 32 μg/ml, 32 μg/ml, 64 μg/ml, and 64 μg/ml, respectively. The postantibiotic effect for (+)-erythro-mefloquine was 36 h (MIC) and 41 h for a concentration of 4× MIC. The mefloquine postantibiotic effect was 25 h (MIC and 4× MIC). After baseline infection was established (7 days), the (+)- and (-)-isomers of the diastereomeric threo- and erythro-α-(2-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol were individually used to orally treat C57BL/6 bg(+)/bg(+) beige mice that were infected intravenously with M. avium. Mice were also treated with commercial mefloquine and diluent as controls. After 4 weeks of treatment, the mice were harvested, and the number of bacteria in spleen and liver was determined. Mice receiving (+)- or (-)-threo-mefloquine or (-)-erythro-mefloquine had numbers of bacterial load in tissues similar to those of untreated control mice at 4 weeks. Commercial mefloquine had a bactericidal effect. However, mice given the (+)-erythro-enantiomer for 4 weeks had a significantly greater reduction of bacterial load than those given mefloquine. Thus, (+)-erythro-mefloquine is the active enantiomer of mefloquine against M. avium and perhaps other mycobacteria.
authors.affiliation: Kuzell Institute for Arthritis and Infectious Diseases, San Francisco, California, USA. luiz.bermudez@oregonstate.edu
authors.forename: Luiz E
authors.initials: LE
authors.lastname: Bermudez
authors.forename: Clark B
authors.initials: CB
authors.lastname: Inderlied
authors.forename: Peter
authors.initials: P
authors.lastname: Kolonoski
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Chee
authors.forename: Priscilla
authors.initials: P
authors.lastname: Aralar
authors.forename: Mary
authors.initials: M
authors.lastname: Petrofsky
authors.forename: Toufan
authors.initials: T
authors.lastname: Parman
authors.forename: Carol E
authors.initials: CE
authors.lastname: Green
authors.forename: Anita H
authors.initials: AH
authors.lastname: Lewin
authors.forename: William Y
authors.initials: WY
authors.lastname: Ellis
authors.forename: Lowell S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058491:Bacterial Load / Q000187:drug effects; D005260:Female; D006801:Humans; D008099:Liver / Q000382:microbiology; D015767:Mefloquine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D015269:Mycobacterium avium Complex / Q000187:drug effects* / Q000302:isolation & purification; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy* / Q000382:microbiology; D013154:Spleen / Q000382:microbiology; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D015767:Mefloquine