Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus
Abstract
:1. Introduction
2. Results and Discussion
2.1. Initial Virtual Screening and Bacterial Assays
2.2. Ability of Analogues of 5376 to Kill Certain Strains of S. aureus
2.3. Molecular Modeling
2.4. Compound 5376 Inhibits M. tuberculosis TrxR Activity and Binding of M. tuberculosis Thioredoxin C (TrxC) to M. tuberculosis TrxR
3. Experimental Section
3.1. Bacterial Species
3.2. Minimum Inhibitory Concentration (MIC)/Minimum Bactericial Concentration (MBC)
3.3. Thioredoxin Reductase-DTNB Assay
3.4. Docking
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
DTNB | Ellman′s Reagent (5,5-dithio-bis-(2-nitrobenzoic acid)) |
DTT | 1,4-Dithiothreitol |
TrxR | Thioredoxin Reductase |
Trx | Thioredoxin |
PDB | Protein Data Bank |
Appendix A
References
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MIC (μg/mL) | ||||||
---|---|---|---|---|---|---|
Compound | S. aureus | E. faecalis | E. coli | P. aeruginosa | M. smegmatis | M. marinum |
8973 | 64 (64) a | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
6702 | 64 (64) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
1108 | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
2628 | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
9010 | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | 128 (128) | >128 (>128) |
1632 | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
5376 | 8 (4-8) | 128 (128) | >128 (>128) | >128 (>128) | 128 (128) | >128 (>128) |
1882 | 32 (32) | 32 (32) | >128 (>128) | >128 (>128) | 128 (128) | >128 (>128) |
3719 | 64 (64) | 128 (128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
Tetracycline | 0.5 (0.25–0.5) | 32 (32) | 2 (1–2) | 16 (16) | ND | ND |
Isoniazid | ND b | ND | ND | ND | 4 | 8 |
MIC (μg/mL) | |||||||||
---|---|---|---|---|---|---|---|---|---|
Compound | ATCC a | MW2 | JE2 | Newman | N315 | MC7606 b | MC7769 | MC7827 | MC7846 |
8973 | >128 c (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
5376 | 8 (4-8) | 4 (4) | 8 (8) | 4 (4) | 4 (2–4) | 2 (2) | 4 (4–8) | 8 (8) | 4 (4) |
5741518 | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
5870804 | 16 (16) | 32 (32) | 32 (32) | 64 (64) | 32 (32) | 4 (4) | 64 (64) | 32 (32–64) | 16 (16) |
2082-0182 | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
2083-1665 | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
2083-1773 | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) | >128 (>128) |
Tetracycline | 0.25 (0.25–0.5) | 0.25 (0.25) | 0.25 (0.25) | 0.25 (0.25) | 0.25 (0.25) | 32 (16–32) | 0.25 (0.25) | 32 (32) | 0.125 (0.125) |
Oxacillin | 0.25 (0.25) | 8 (8–16) | 8 (8–6) | 0.5 (0.5) | 16 (16) | 4 (4) | 4 (4) | 4 (4) | 4 (4–8) |
Vancomycin | 0.5 (0.5) | 1 (1) | 1 (1) | 1 (1) | 1 (1) | 1 (1) | 1 (1) | 1 (1) | 4 (4) |
Compound | R | X | Y | MIC (µg/mL) MC7606 | MIC (µg/mL) MC7769 | MIC (µg/mL) MC7827 | MIC (µg/mL) MC7846 | Docking Energy (kcal/mol) |
---|---|---|---|---|---|---|---|---|
5376 | O | 4-Br | 4-Cl | 2 | 4 | 8 | 4 | −9.3 |
5741518 | O | 4-CH3 | 4-Cl | >128 | >128 | >128 | >128 | −8.7 |
5870804 | O | 4-Br | H | 4 | 64 | 32 | 16 | −10.9 |
2082-0182 | O | H | 4-Cl | >128 | >128 | >128 | >128 | −9.0 |
2083-1665 | OCH3 | 4-Br | 4-Cl | >128 | >128 | >128 | >128 | −8.6 |
2083-1773 | O | 3-Br | 4-Cl | >128 | >128 | >128 | >128 | −9.8 |
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Sweeney, N.L.; Lipker, L.; Hanson, A.M.; Bohl, C.J.; Engel, K.E.; Kalous, K.S.; Stemper, M.E.; Sem, D.S.; Schwan, W.R. Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus. Antibiotics 2017, 6, 4. https://doi.org/10.3390/antibiotics6010004
Sweeney NL, Lipker L, Hanson AM, Bohl CJ, Engel KE, Kalous KS, Stemper ME, Sem DS, Schwan WR. Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus. Antibiotics. 2017; 6(1):4. https://doi.org/10.3390/antibiotics6010004
Chicago/Turabian StyleSweeney, Noreena L., Lauren Lipker, Alicia M. Hanson, Chris J. Bohl, Katie E. Engel, Kelsey S. Kalous, Mary E. Stemper, Daniel S. Sem, and William R. Schwan. 2017. "Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus" Antibiotics 6, no. 1: 4. https://doi.org/10.3390/antibiotics6010004
APA StyleSweeney, N. L., Lipker, L., Hanson, A. M., Bohl, C. J., Engel, K. E., Kalous, K. S., Stemper, M. E., Sem, D. S., & Schwan, W. R. (2017). Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus. Antibiotics, 6(1), 4. https://doi.org/10.3390/antibiotics6010004