Mefloquine and Its Enantiomers Are Active againstMycobacterium tuberculosisIn Vitro and in Macrophages

Abstract

Objective. Tuberculosis is a serious problem of public health. The increase on the number of clinical cases of tuberculosis infected with multidrug resistant (MDR) M. tuberculosis calls for the development of novel therapy. Design. We investigated the effect of mefloquine and two enantiomers, (+)erythro-mefloquine and (+)threo-mefloquine against M. tuberculosis strains in the environment resembling the aspects of the granuloma environment and in macrophages. Results. The results suggest that mefloquine (racemic mixture) and (+)erythro-mefloquine have bactericidal activity against M. tuberculosis strains both in acidic, low oxygen tension and in macrophages. The activity, however, was impaired under increased osmolarity. Conclusion. Identification of the target for mefloquine in the pathogen will allow for the development of novel drugs with antituberculosis activity.

Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters

“…Limited data on the in vitro activity of mefloquine against M. tuberculosis have documented MICs ranging from 8 to 16 mg/L, 18,19 and our study validates these findings. Serum levels of mefloquine range from 1 to 2 mg/L at standard dosing for malaria (Table 3), which is well below the demonstrated MICs.…”

“…But studies have indicated that mefloquine concentrates in macrophages to levels Cavanaugh et al DST of MDR-TB isolates JAC above the MICs. 18,20 If this finding can be substantiated, then mefloquine may have clinical utility in the treatment of drug-resistant TB, and further clinical investigation would be warranted.…”

Primaquine derivatives: Modifications of the terminal amino group

“…Drug repositioning or repurposing, i.e. finding new indications for existing/approved drugs, is an increasingly utilized strategy in search of novel medicines [3,4], for example antiparasitic [5,6] and antimycobacterial use of antimalarial drugs [7,8]. Repurposing of antimalarial drugs as anticancer agents is particularly interesting, since different classes of antimalarials display either direct or adjuvant activity against cancer, act as sensitivity reversers of resistant tumour cell lines, inhibitors of drug resistance development, or synergistic agents with known anticancer drugs [9e22].…”

Synthesis and Study of New Quinolineaminoethanols as Anti-Bacterial Drugs

“…Despite their structural similarity, these two quinolines possess two different antimicrobial spectra. BQ 2a is only active against mycobacteria [7,14] in the nanomolar range, while MQ 1a/1b is active against Plasmodium falciparum in the nanomolar range and Gram-positive bacteria and mycobacteria in the micromolar range (Figure 1) [9,15,16,17]. ( R , S )-BQ 2a targets very specific mycobacteria, including M. tuberculosis and M. avium [14], due to its great affinity to the mycobacteria F0F1-ATP synthase [18].…”

“…However, some biochemical evidence has associated the antibacterial properties of MQ to its interaction with the F0F1-ATP synthase [21]. Even if MQ 1a/1b is used as racemic mixture, studies suggest this is the best activity of the enantiomer (+)-( S , R )-MQ compared to its optical antipode against P. falciparum and M. tuberculosis in vitro and M. avium in vivo [16,17,23]. However, this difference in activity is not observed against bacteria such as S. aureus , Enterococcus faecalis or Streptococcus pneumonia [9,21].…”