Short, Synthetic Cationic Peptides Have Antibacterial Activity against Mycobacterium smegmatis by Forming Pores in Membrane and Synergizing with Antibiotics
Abstract
:1. Introduction
2. Materials and Methods
2.1. Bacterial and Mammalian Cells
2.2. Peptides
2.3. Bioinformatics
2.4. Bactericidal Assays
2.5. Minimum Inhibitory Concentration (MIC) Measurements
2.6. Checkerboard Assay
2.7. Bacterial Cytoplasmic Membrane Depolarization Assay
2.8. Bacterial Cytoplasmic Membrane Permeation
2.9. In Vitro Intracellular Activity in Infected Macrophages
3. Results
3.1. Synthetic ATRA Peptides Exert Antimycobacterial Effects
Peptide | Sequence | Net Charge at pH 7 | Hydro-Phobicity |
---|---|---|---|
NA-CATH | KRFKKFFKKLKNSVKKRAKKFFKKPKVIGVTFPF (ATRA-1) (ATRA-2) | +15 | 38% |
ATRA-1A | KRAKKFFKKLK-NH2 | +8 | 36% |
ATRA-2 | KRAKKFFKKPK-NH2 | +8 | 27% |
hBD3-Pep4 | RGRRSSRRKK-NH2 | +7 | 0% |
mCRAMP | GLLRKGGEKIGEKLKKIGQKIKNFFQKLVPQPEQ | +6 | 29% |
LL-37 | LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES | +6 | 35% |
Peptide/Antibiotic | Molecular Weight (g/mol) | EC50 | Fold vs. Rifampicin | ||
---|---|---|---|---|---|
μg/mL | 95% Confidence Interval | μM | |||
Rifampicin | 822.94 | 0.13 | 0.061 to 0.276 | 0.159 | 1.0 |
Polymyxin B | 1301.56 | 0.12 | 0.086 to 0.180 | 0.096 | 1.65 |
Fosmidomycin | 183.1 | 0.14 | 0.062 to 0.326 | 0.780 | 0.20 |
NA-CATH | 4175.26 | 1.88 | 0.622 to 5.68 | 0.451 | 0.354 |
hBD3-Pep4 | 1286.51 | 0.36 | 0.159 to 0.824 | 0.287 | 0.554 |
LL-37 | 7793.33 | 0.27 | 0.150 to 0.491 | 0.060 | 2.65 |
mCRAMP | 3878.67 | 0.17 | 0.093 to 0.325 | 0.044 | 3.61 |
ATRA-1A | 1420.84 | 0.05 | 0.034 to 0.075 | 0.035 | 4.54 |
ATRA-2 | 1404.80 | >100 | - | - | - |
3.2. Cathelicidin Peptides mCRAMP, NA-CATH, and LL-37 Are Antimycobacterial
3.3. Human β-Defensin Derivative hBD3-Pep4 Exerts Antimycobacterial Activity
3.4. Minimum Inhibitory Concentration of Peptides to Inhibit Mycobacterial Growth
Peptide/Antibiotic | MIC (μg/mL) | MIC μM | Fold vs. Rifampicin (μM) |
---|---|---|---|
Rifampicin | 3.9 | 4.73 | 1 |
Fosmidomycin | 7.8 | 1.86 | 0.39 |
Polymyxin B | 7.8 | 5.99 | 1.26 |
mCRAMP | 15.6 | 4.02 | 0.85 |
LL-37 | 31.3 | 4.01 | 0.85 |
ATRA-1A | 31.3 | 22.01 | 5.11 |
hBD3-Pep4 | 62.6 | 48.65 | 10.28 |
NA-CATH | 250 | 59.80 | 12.64 |
ATRA-2 | >125 | - | - |
3.5. Membrane Permeablization and Depolarization by Peptides
3.6. Synergy with Antibiotics
Drug Combination | MIC (μg/mL) | FIC | FICI | |
---|---|---|---|---|
Alone | Combined | |||
Rifampicin ATRA-1A | 3.9 | 1.95 | 0.5 | 0.56 |
31.3 | 3.9 | 0.06 | ||
Rifampicin hBD3-Pep4 | 3.9 | 1.95 | 0.5 | 0.56 |
62.6 | 3.9 | 0.06 | ||
Rifampicin LL-37 | 3.9 | 0.97 | 0.25 | 0.32 |
31.3 | 3.9 | 0.12 | ||
Rifampicin mCRAMP | 3.9 | 0.97 | 0.25 | 0.35 |
15.6 | 1.95 | 0.12 | ||
Polymyxin B ATRA-1A | 7.8 | 1.95 | 0.5 | 0.37 |
31.3 | 3.9 | 0.12 | ||
Polymyxin B hBD3-Pep 4 | 7.8 | 1.95 | 0.25 | 0.37 |
62.6 | 7.8 | 0.12 | ||
Polymyxin B LL-37 | 7.8 | 1.95 | 0.25 | 0.37 |
31.3 | 3.9 | 0.12 | ||
Polymyxin B mCRAMP | 7.8 | 1.95 | 0.25 | 0.5 |
15.6 | 3.9 | 0.25 |
3.7. Intracellular Killing of Mycobacteria Peptide-Treated Macrophages
4. Discussion
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Gupta, K.; Singh, S.; Van Hoek, M.L. Short, Synthetic Cationic Peptides Have Antibacterial Activity against Mycobacterium smegmatis by Forming Pores in Membrane and Synergizing with Antibiotics. Antibiotics 2015, 4, 358-378. https://doi.org/10.3390/antibiotics4030358
Gupta K, Singh S, Van Hoek ML. Short, Synthetic Cationic Peptides Have Antibacterial Activity against Mycobacterium smegmatis by Forming Pores in Membrane and Synergizing with Antibiotics. Antibiotics. 2015; 4(3):358-378. https://doi.org/10.3390/antibiotics4030358
Chicago/Turabian StyleGupta, Kajal, Sameer Singh, and Monique L. Van Hoek. 2015. "Short, Synthetic Cationic Peptides Have Antibacterial Activity against Mycobacterium smegmatis by Forming Pores in Membrane and Synergizing with Antibiotics" Antibiotics 4, no. 3: 358-378. https://doi.org/10.3390/antibiotics4030358