Figure 1.
Biosynthetic pathways and structures of inhibitors.
(A) Biosynthesis of ergosterol, cholesterol and staphyloxanthin. (B) Structures of inhibitors of interest.
Table 1.
Summary of data processing and refinement statistics of TcSQS complex crystals.
Table 2.
Summary of data processing and refinement statistics of HsSQS complex crystals.
Table 3.
Summary of data processing and refinement statistics of HsSQS complex crystals.
Figure 2.
Structural comparisons between TcSQS and HsSQS.
(A) Overall structure of TcSQS in complex with FSPP. TcSQS and FSPP are shown in cyan ribbon and purple sticks, respectively. (B) As (A) but for HsSQS in green ribbon (SQS) and yellow sticks (FSPP). (C) Superimposition of TcSQS/FSPP (cyan/purple) and HsSQS/FSPP (green/yellow) structures. (D) Stereo view of FSPP and TcSQS amino-acid residues. FSPP ligands are in purple sticks. (E) Superimposition of FSPP ligands in TcSQS (green and yellow) and HsSQS (blue and magenta).
Figure 3.
Crystal structures of E5700 and ER119884 bound to TcSQS and HsSQS.
(A) TcSQS/E5700 (PDB ID code 3WCC) superimposed on TcSQS/FSPP (PDB ID code 3WCA), E5700 in cyan, FSPP in green and yellow. (B) TcSQS/ER119884 (PDB ID code 3WCE) superimposed on TcSQS/FSPP (PDB code ID 3WCA). ER119884 in blue, FSPP in green and yellow. (C) Superimposed Tc/Hs SQS structures with E5700 (PDB ID codes 3WCC and 3WCJ), showing protein residues of interest. TcSQS in cyan, HsSQS in orange. (D) Superimposed Tc/Hs SQS structures with ER119884 (PDB ID codes 3WCE and 3WCM), showing protein residues of interest. TcSQS in blue, HsSQS in yellow.
Figure 4.
Enzyme and cell growth inhibition results.
(A) TcSQS and HsSQS inhibition by bisphosphonates as a function of n, the number of carbons in the n-alkyl group. For n<6, the IC50 values are larger than 10 µM; (B) As (A) but for TcFPPS and HsFPPS. (C) T. cruzi amastigote cell growth inhibition by bisphosphonates as a function of n. (D) Isobologram showing the synergistic effect of E5700 and posaconazole against T. cruzi amastigotes after 96 h of treatment. Dashed line corresponds to the predicted positions of the experimental points for additive effects.
Table 4.
IC50 values (in µM) for lipophilic bisphosphonates inhibiting T. cruzi and human SQS and FPPS, T. cruzi amastigote cell growth and Vero (host) cell growtha.
Figure 5.
Complex Structures of SQS with lipophilic bisphosphonate inhibitors.
(A) TcSQS/BPH-1237; (B) TcSQS/BPH-1344; (C) HsSQS/BPH-1237; (D) HsSQS/BPH-1344; (E) HsSQS/BPH-1218; (F) HsSQS/BPH-1325. All structures are superimposed on the corresponding FSPP structures (shown in green and yellow).
Figure 6.
Structures of WC-9 bound to HsSQS and CrtM.
(A) Stereo view of WC-9 bound to HsSQS. The 2Fo - Fc map is contoured at 1σ. (B) Structure of WC-9 bound to CrtM (yellow), overlaid with WC-9/HsSQS structure (blue).
Figure 7.
Comparisons between TcSQS/E5700 and CrtM/inhibitor structures.
The CrtM inhibitors are: (A) BPH-651 (PDB ID code 3ACW). (B) SQ-109 (PDB ID code 4EA2). (C) BPH-702 (PDB ID code 3ACY). (D) BPH-652 (PDB ID code 2ZCQ).