Replacement of l-Amino Acids by d-Amino Acids in the Antimicrobial Peptide Ranalexin and Its Consequences for Antimicrobial Activity and Biodistribution
Abstract
1. Introduction
2. Results
2.1. Peptide Synthesis
2.2. Antimicrobial Susceptibility of Clinical Isolates
2.3. Antimicrobial Activity of Ranalexin and Danalexin
2.4. Time-Kill Curves
2.5. Scintigraphy
2.6. Micro-PET Imaging
3. Discussion
4. Material and Methods
4.1. Peptide Synthesis
4.2. Antimicrobial Activity
4.3. Time-Kill Curves
4.4. Radioactive Labeling and In Vivo Imaging
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds tested in this study are available from the authors. |
Peptide | Amino Acid Sequence | |||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ranalexin | F | L | G | G | L | I | K | I | V | P | A | M | I | C | A | V | T | K | K | C |
Ranalexin-d-Tyr | F | L | G | G | L | I | K | I | V | P | A | M | I | C | A | V | y1 | K | K | C |
Danalexin | f | l | G | G | l | i | k | i | v | p | a | m | i | c | a | v | t | k | k | c |
d-Tyr-danalexin | Y 1 | l | G | G | l | i | k | i | v | p | a | m | i | c | a | v | t | k | k | c |
DOTA-d-Tyr-danalexin | y | l | G | G | l | i | k | i | v | p | a | m | i | c | a | v | t | k | K 2 | c |
Peptide | Calculated Mass [Da] | Observed Mass [Da] | Detected Species |
---|---|---|---|
Ranalexin | 2103.1890 | 2104.1768 | [M + H]+ |
Ranalexin-d-Tyr | 2165.0267 | 1083.6002 | [M + 2H]2+ |
Danalexin | 2103.1890 | 2104.1047 | [M + H]+ |
d-Tyr-danalexin | 2119.1839 | 2120.1700 | [M + H]+ |
DOTA-d-Tyr-danalexin | 2506.0098 | 2506.1562 | [M]+ |
A. baumannii SC303336 4-MRGN | A. baumannii SC411190 4-MRGN, OXA-23 | E. faecium UL407074 VanA | K. pneumoniae BL809453 4-MRGN, KPC | |
---|---|---|---|---|
Amoxicillin/Clavulanic acid | nt | R | R | nt |
Piperacillin | R | R | nt | R |
Piperacillin/Tazobactam | R | R | nt | R |
Cefuroxime | nt | nt | R | R |
Imipenem | R | R | R | R |
Meropenem | R | R | nt | R |
Ciprofloxacin | R | R | R | R |
Gentamicin | R | R | nt | I |
Tobramycin | R | R | nt | R |
Amikacin | R | R | nt | nt |
Tigecycline | I | nt | S | S |
Trimethoprim/Sulfamethoxazole | R | R | R | R |
Vancomycin | nt | nt | R | nt |
Teicoplanin | nt | nt | R | nt |
Erythromycin | nt | nt | R | nt |
Linezolid | nt | nt | S | nt |
Colistin | S | S | nt | S |
Bacterium | MIC [mg/L] (µM) | ||
---|---|---|---|
Ranalexin | Danalexin | Positive Control | |
Gram-positive bacteria | |||
Bacillus megaterium DSM 32 | 4 (1.9) | 4 (1.9) | vancomycin 0.13 |
B. subtilis DSM 10 | 4 (1.9) | 4 (1.9) | vancomycin 0.13 |
Clostridium pasterianum DSM 525 | 16 (7.6) | 8 (3.8) | vancomycin 0.25 |
Corynebacterium spheniscorum DSM 44757 | 16 (7.6) | 8 (3.8) | vancomycin 0.50 |
Enterococcus casseliflavus ATCC 700327 VanC 1 | 8 (3.8) | 8 (3.8) | vancomycin 8 |
E. faecalis ATCC 29212 | 16 (7.6) | 16 (7.6) | vancomycin 1 |
E. faecium UL4070742 VanA 3 | 16 (7.6) | 8 (3.8) | vancomycin 640 |
Staphylococcus aureus ATCC 25923 | 8 (3.8) | 4 (1.9) | vancomycin 1 |
S. aureus NCTC 10442 MRSA 4 | 8 (3.8) | 8 (3.8) | vancomycin 1 |
S. epidermidis ATCC 14990 | 16 (7.6) | 16 (7.6) | vancomycin 2 |
S. saprophyticus ATCC 15305 | 8 (3.8) | 16 (7.6) | vancomycin 2 |
Gram-negative bacteria | |||
Acinetobacter baumannii SC3033362 4-MRGN 5 | 4 (1.9) | 4 (1.9) | colistin 0.25 6 |
A. baumannii SC3223332 4-MRGN 5 | 8 (3.8) | 16 (7.6) | colistin 1 6 |
A. baumannii SC4111902 4-MRGN 5 | 4 (1.9) | 8 (3.8) | colistin 0.25 6 |
Escherichia coli ATCC 25922 | 32 (15.2) | 32 (15.2) | colistin 0.25 6 |
E. coli 0157:H7 ATCC 35150 EHEC 7 | 32 (15.2) | 32 (15.2) | colistin 0.50 6 |
Klebsiella pneumoniae ATCC 700603 | >64 (>30.4) | >64 (>30.4) | colistin 1 6 |
K. pneumoniae BL809453 2 | >64 (>30.4) | >64 (>30.4) | colistin 0.25 6 |
Pseudomonas aeruginosa ATCC 27853 | 64 (30.4) | 64 (30.4) | colistin 0.25 6 |
P. fluorescens DSM 50090 | >64 (>30.4) | >64 (>30.4) | doxycycline 0.50 |
Yersinia mollaretii DSM 18520 | >64 (>30.4) | >64 (>30.4) | colistin 0.25 6 |
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Domhan, C.; Uhl, P.; Kleist, C.; Zimmermann, S.; Umstätter, F.; Leotta, K.; Mier, W.; Wink, M. Replacement of l-Amino Acids by d-Amino Acids in the Antimicrobial Peptide Ranalexin and Its Consequences for Antimicrobial Activity and Biodistribution. Molecules 2019, 24, 2987. https://doi.org/10.3390/molecules24162987
Domhan C, Uhl P, Kleist C, Zimmermann S, Umstätter F, Leotta K, Mier W, Wink M. Replacement of l-Amino Acids by d-Amino Acids in the Antimicrobial Peptide Ranalexin and Its Consequences for Antimicrobial Activity and Biodistribution. Molecules. 2019; 24(16):2987. https://doi.org/10.3390/molecules24162987
Chicago/Turabian StyleDomhan, Cornelius, Philipp Uhl, Christian Kleist, Stefan Zimmermann, Florian Umstätter, Karin Leotta, Walter Mier, and Michael Wink. 2019. "Replacement of l-Amino Acids by d-Amino Acids in the Antimicrobial Peptide Ranalexin and Its Consequences for Antimicrobial Activity and Biodistribution" Molecules 24, no. 16: 2987. https://doi.org/10.3390/molecules24162987
APA StyleDomhan, C., Uhl, P., Kleist, C., Zimmermann, S., Umstätter, F., Leotta, K., Mier, W., & Wink, M. (2019). Replacement of l-Amino Acids by d-Amino Acids in the Antimicrobial Peptide Ranalexin and Its Consequences for Antimicrobial Activity and Biodistribution. Molecules, 24(16), 2987. https://doi.org/10.3390/molecules24162987