Selective Action of Fluoroquinolones Against Intracellular Amastigotes of Leishmania (Viannia) Panamensis in Vitro

Abstract

We have demonstrated that fluoroquinolones, a class of antibacterial agents that act through inhibition of type II DNA topoisomerases, exert selective action against intracellular amastigotes of Leishmania (Viannia) panamensis at concentrations that are achievable in vivo. Drug cytotoxicity assays employing the luciferase reporter gene revealed that intracellular amastigotes were 6.6- to 25.9-fold more sensitive than human macrophages (P < 0.05) to second-generation fluoroquinolones in vitro. The most selective agents (enoxacin and ciprofloxacin) exhibited 2 orders of magnitude greater potency against parasites (50% effective dose [ED50] = 54.9-83.4 microM) than host cells (ED50 = 1,425-1,740 microM). Linear regression analysis of ED50 data confirmed a complete lack of correlation (r = 0.001) between the relative drug sensitivities of parasites and host cells. A potential relationship between the structures of fluoroquinolones and their relative leishmanicidal activities was observed. The key substituents of the basic pyridone beta-carboxylic acid nucleus accounting for enhanced antiparasite potency and selectivity appear to be a nitrogen at position 8 of the bicyclic nucleus (enoxacin), a cyclopropyl substituent at the R1 site (ciprofloxacin), and linkage of the R1 and X8 groups by a CH3CHO bridge to form a tricyclic compound (ofloxacin). These findings support the potential of fluoroquinolones and derivatives as novel antileishmanials and encourage their clinical evaluation.

Transferable mechanisms of quinolone resistance

“…Moreover, some FQs possess activity against eukaryotic targets and have been studied as a possible novel antiparasitic treatment [10,11] or explored as potential antineoplastic agents [12]. Finally, quinolones have been extensively used in veterinary practice [13,14].…”

Topoisomerase II from Human Malaria Parasites

“…These results are consistent with the idea that the etoposide target is the nuclear-localized PfTopoII, although the challenge is to understand how this particular class of TopoII inhibitors may be optimized and deployed with selectivity. Ciprofloxacin, heavily used as an antibacterial, has previously been tested as an experimental inhibitor of P. falciparum (53)(54)(55)(56), Trypanosoma brucei (57), and Leishmania panamensis (16,58). In those studies, without structural optimization, the compound showed more than 70-fold selective inhibition of parasite cells over human macrophage cells (Table 2).…”

Upregulation of Cysteine Synthase and Cystathionine β-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress

“…Monocytes were harvested during the logarithmic stage of growth and transferred to medium containing 50 ng/ml phorbol myristate acetate (PMA; Sigma) as an inductor of adherence and differentiation into macrophages. For assay of in vitro infection by L. braziliensis, a total of 1 ϫ 10 5 cells were transferred to a 6-well plate and incubated for 72 h at 37°C in a 5% CO 2 atmosphere (30).…”

“…Parasites from stationary growth phase were harvested after 6 days of passage and opsonized by treatment with RPMI 1640 containing 10% human type AB-positive serum for 1 h as described elsewhere (30). Infection of the macrophages was performed for 2 h at 34°C in a 5% CO 2 atmosphere using a parasite-to-cell ratio of 20:1, following removal of nonadherent parasites by washing the plate well twice with phosphate-buffered saline (PBS).…”