Title : Sensitivity of Antimony(III)-Sensitive and -Resistant MRPA-Overexpressing and AQP1-Mutated Leishmania Strains towards Novel Organoantimony(V) and Organobismuth(V) complexes and their effect on DNA and membrane Integrity
Abstract:
The aim the present study was to investigate the impact of novel pentavalent organobismuth and organoantimony complexes on membrane integrity and their interaction with DNA, activity against Sb(III)?sensitive and ?resistant Leishmania strains and toxicity in mammalian peritoneal macrophages. Ph 3M(L) 2 type complexes were synthesized, where M = Sb(V) or Bi(V) and L = deprotonated 3?(dimethylamino) benzoic acid or 2?acetylbenzoic acid. Both organobismuth(V) and organoantimony(V) complexes exhibited efficacy at micromolar concentrations against Leishmania amazonensis and L. infantum but only the later ones demonstrated biocompatibility. Ph 3Sb(L1)2 and Ph 3Bi(L1) 2 demonstrated distinct susceptibility profiles compared to inorganic Sb(III)?resistant strains of MRPA?overexpressing L. amazonensis and AQP1? mutated L. guyanensis. These complexes were able to permeate the cell membraneand interact with the Leishmania DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis. Taken altogether, our data substantiate the notion of a distinct mechanism of uptake pathway and action in Leishmania for these organometallic complexes, distinguishing them from the conventional inorganic antimonial drugs.
