Resistance of Leishmania donovani to sodium stibogluconate is related to the expression of host and parasite γ-glutamylcysteine synthetase

摘要: Sequencing studies showed that the γ-glutamylcysteine synthetase (γ-GCS) heavy chain genes from sodium stibogluconate (SSG)-resistant (SSG-R) and SSG-susceptible (SSG-S) Leishmania donovani strains were identical, indicating that SSG resistance was related to quantitative differences in γ-GCS expression rather than gene interstrain polymorphisms. In vitro infection of murine macrophages with the SSG-R strain, but not the SSG-S strain, down regulated expression of host γ-GCS, which would result in a reduction in intramacrophage glutathione (GSH) levels and promote an oxidative intramacrophage environment. This would inhibit, or minimize, the reduction of SSG pentavalent antimony to its more toxic trivalent form. Macrophage studies showed that the SSG-R strain expressed higher levels of γ-GCS compared to the SSG-S strain, which would result in higher GSH levels, giving increased protection …