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Title
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In vitro susceptibilities of **Leishmania donovani** promastigote and amastigote stages to antileishmania reference drugs: practical relevance of stage-specific differences
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Author
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Abstract
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| The in vitro susceptibility of the reference strain Leishmania donovani MHOM/ET/67/L82 to sodium stibogluconate, amphotericin B, miltefosine and the experimental compound PX-6518, was determined for the extracellular log-phase promastigotes, established axenic amastigotes and fresh spleen-derived amastigotes, and intracellular amastigotes in primary mouse peritoneal macrophages. Amphotericin B susceptibility did not differ across the various axenic models (IC50 0.6 - 0.7 µM) and showed slightly higher potency against intracellular amastigotes (IC50 0.1 - 0.4 µM). A similar trend was observed for miltefosine with comparable efficacy against the extracellular (IC50 0.4 - 3.8 µM) and intracellular (IC50 0.9 - 4.3 µM) stages. Sodium stibogluconate, either used as Pentostam® or as crystalline substance was inactive against all axenic stages (IC50 >64 µg SbV/ml) but showed good efficacy against intracellular amastigotes (IC50 22-28 µg SbV/ml), with the crystalline substance being about 2 to 3 times more potent (IC50 9-11 µg SbV/ml). The activity profile of PX-6518 was comparable to sodium stibogluconate, be it at much higher potency (IC50 0.1 µg/ml). In conclusion, the differential susceptibility determines which in vitro models are appropriate for either drug screening or resistance monitoring in clinical field isolates. Despite the more complex and labour-intensive protocol, current results support the intracellular amastigote model as the golden standard for in vitro Leishmania drug discovery research and evaluation of resistance in field strains since it also includes host cell-mediated effects. Axenic systems can only be recommended for compounds for which no cellular mechanisms are involved, for example, amphotericin B and miltefosine |
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Language
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English
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Source (journal)
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Antimicrobial agents and chemotherapy. - Washington, D.C., 1972, currens
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Publication
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Washington, D.C.
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American Society for Microbiology
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2009
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ISSN
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0066-4804
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DOI
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10.1128/AAC.00548-09
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Volume/pages
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53
:9
(2009)
, p. 3855-3859
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ISI
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000270014200032
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Full text (Publisher's DOI)
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