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Background  The enzyme farnesyl diphosphate synthase (FPPS) is positioned in the intersection of different sterol biosynthesis pathways such as those producing isoprenoids, dolichols and ergosterol. FPPS is ubiquitous in eukaryotes and is inhibited by nitrogen-containing bisphosphonates (N-BP). N-BP activity and the mechanisms of cell death as well as damage to the ultrastructure due to N-BP has not yet been investigated in  Leishmania infantum  and  Giardia . Thus, we evaluated the effect of N-BP on cell viability and ultrastructure and then performed structural modelling and phylogenetic analysis on the FPPS enzymes of  Leishmania  and  Giardia .    Methods  We performed multiple sequence alignment with MAFFT, phylogenetic analysis with MEGA7, and 3D structural modelling for FPPS with Modeller 9.18 and on I-Tasser server. We performed concentration curves with N-BP in  Leishmania  promastigotes and  Giardia  trophozoites to estimate the IC 50  via  the MTS/PMS viability method. The ultrastructure was evaluated by transmission electron microscopy, and the mechanism of cell death by flow cytometry.    Results  The nitrogen-containing bisphosphonate risedronate had stronger anti-proliferative activity in  Leishmania  compared to other N-BPs with an IC 50  of 13.8 µM, followed by ibandronate and alendronate with IC 50  values of 85.1 µM and 112.2 µM, respectively. The effect of N-BPs was much lower on trophozoites of  Giardia  than  Leishmania  (IC 50  of 311 µM for risedronate).  Giardia  treated with N-BP displayed concentric membranes around the nucleus and nuclear pyknosis.  Leishmania  had mitochondrial swelling, myelin figures, double membranes, and plasma membrane blebbing. The same population labelled with annexin-V and 7-AAD had a loss of membrane potential (TMRE), indicative of apoptosis. Multiple sequence alignments and structural alignments of FPPS proteins showed that  Giardia  and  Leishmania  FPPS display low amino acid identity but possess the conserved aspartate-rich motifs.    Conclusions   Giardia  and  Leishmania  FPPS enzymes are phylogenetically distant but display conserved protein signatures. The N-BPs effect on FPPS was more pronounced in  Leishmania  than  Giardia . This might be due to general differences in metabolism and differences in the FPPS catalytic site.

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Insights about the structure of farnesyl diphosphate synthase (FPPS) and the activity of bisphosphonates on the proliferation and ultrastructure of Leishmania and Giardia