Covalent Conjugates of Allylbenzenes and Terpenoids as Antibiotics Enhancers with the Function of Prolonged Action
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis and Characterization of Covalent and Non-Covalent Antibacterial Formulations
- (1)
- Synthesis and characterization by FTIR and NMR spectroscopy of the covalent conjugates of MF, allylbenzenes (EG and apiol), terpenoids (linalool and limonene) with polymers (based on PEI, chitosan, mannan), with a variable type of covalent linkage (amide or ester bond) and with a variable crosslinking agent, to determine the most efficient and optimal composition of the antibacterial conjugate.
- (2)
- Incorporation of the drug composition into polymer nanogels followed by covalent crosslinking of the particles, without involving the drug in covalent bonds.
- (3)
- Investigation of the antibacterial activity (against E. coli and B. subtilis) of the developed prodrugs in terms of efficiency and duration of their action.
- (4)
- Elucidation of the mechanisms of the conjugate action in cells using FTIR spectroscopy in comparison with free antibacterials.
- (5)
- Study of the pharmacokinetics of the antibacterial covalent prodrugs in comparison with the antibacterial formulations included in nanogels (non-covalent prodrugs).
2.1.1. MF Covalent Prodrug Formulations Synthesis and Characterization by FTIR and NMR Spectroscopy
2.1.2. Allylbenzenes and Terpenoids Formulations
2.1.3. Non-Covalent Formulations of MF, Allylbenzenes and Terpenoids with Glycol–Chitosan Hydrogels Stabilized by Crosslinking Bifunctional Agents
2.2. Antibacterial Activity of MF, Allylbenzenes, Terpenoids
2.2.1. Primary High-Throughput Screening of the Antibacterial Activity of Prodrug Conjugates
2.2.2. Prolonged Antibacterial Experiment with the Most Promising Formulations
2.3. FTIR Spectroscopy as a Tool for Tracking Drug Penetration into Cells and Its Effectiveness
2.4. FTIR Spectroscopy as a Tool for Determining the Number of Cells in Antibacterial Experiments
2.5. Pharmacokinetics of MF in Polymer Particles and Covalent Conjugates
3. Materials and Methods
3.1. Reagents
3.2. HPCD–PEI1.8–triMan Polymer Synthesis and Properties
3.3. MF Conjugation with Polymers
3.4. Preparation of MF Non-Concovalent Formulations
3.5. Adjuvant Conjugation with Polymers
3.6. FTIR Spectroscopy
3.7. NMR Spectroscopy
3.8. Antibacterial Activity Studies: FTIR Spectroscopy, Microbiology
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
EG | eugenol |
GlycChit | glycol chitosan |
HPCD | (2-hydroxypropyl)-β-cyclodextrin |
IC50 | Half-maximal inhibitory concentration |
MF | moxifloxacin |
PEI | polyethyleneimine |
triMan | mannotriose residue |
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Designation | Chemical Composition | MF Percentage *, % |
---|---|---|
MF | MF free | 100 |
MF1 | MF–HPCD–PEI1.8-triMan (covalent), 13 MF molecule on polymer | 34 ± 5 |
MF2 | MF–GlycChit (covalent), 1 MF molecule accounts for 2.4 glucosamine unit | 45 ± 3 |
MF3 | MF–Mannan (covalent), 1 MF molecule accounts for 5.3 mannose unit | 32 ± 2 |
MF-gel1 | MF + GlycChit genipin-stitched (non-covalent) | 72 ± 4 |
MF-gel2 | MF + GlycChit-acetylcysteine S-S stitched (non-covalent) | 69 ± 3 |
Designation * | IC50 against E. coli, ng/mL | IC50 against B. subtilis, ng/mL |
---|---|---|
MF | 8 ± 2 | 800 ± 300 |
MF1 | 40 ± 7 | 11 ± 3 |
MF2 | 4 ± 1 | 9 ± 2 |
MF3 | 3 ± 1 | 10 ± 3 |
MF-gel1 | 7 ± 2 | 20 ± 5 |
MF-gel2 | 7 ± 2 | 15 ± 4 |
E. coli | B. subtilis | |||||
---|---|---|---|---|---|---|
Compound X | X-Covalent with HPCD–PEI1.8–triMan (X-Polymer) | MF Free 30 ng/mL * + X-Covalent with HPCD–PEI1.8–triMan | X + GlycChit Genipin-Stitched (X-gel) | X-Covalent with HPCD–PEI1.8–triMan (X-Polymer) | MF Free 30 ng/mL ** + X-Covalent with HPCD–PEI1.8–triMan | X + GlycChit Genipin-Stitched (X-Gel) |
EG | 64 ± 7 | 41 ± 3 | 85 ± 11 | 81 ± 8 | 60 ± 7 | 94 ± 3 |
Apiol | 75 ± 9 | 44 ± 5 | 92 ± 8 | 81 ± 7 | 59 ± 7 | 93 ± 4 |
Linalool | 85 ± 6 | 47 ± 4 | 93 ± 7 | 85 ± 9 | 62 ± 5 | 97 ± 2 |
Limonene | 74 ± 9 | 46 ± 2 | 94 ± 5 | 83 ± 6 | 59 ± 7 | 89 ± 5 |
Parameters | MF Free | MF + HPCD–PEI1.8–triMan (Non-Covalent) | MF + EG + HPCD–PEI1.8–triMan (Non-Covalent) | MF + Apiol + HPCD–PEI1.8–triMan (Non-Covalent) | MF–Mannan (Covalent) | MF + Mannan (Mixture) |
---|---|---|---|---|---|---|
Half-distribution period, min | 20 ± 2 | 15 ± 1 | 12 ± 2 | 25 ± 4 | 15 ± 2 | 14 ± 2 |
Half-elimination period, h | 6.5 ± 0.5 | 10 ± 1 | 22 ± 2 | 45 ± 6 | 42 ± 7 | 24 ± 3 |
Kinetical distribution volume, L | 8 ± 1 | 4 ± 1 | 4 ± 1 | 3 ± 1 | 3 ± 1 | 3 ± 1 |
Stationary distribution volume, L | 4 ± 1 | 4 ± 1 | 4 ± 1 | 3 ± 1 | 3 ± 1 | 3 ± 1 |
Clearance, mL/min | 14 ± 2 | 4.5 ± 0.6 | 2.0 ± 0.4 | 0.9 ± 0.2 | 0.8 ± 0.1 | 1.3 ± 0.3 |
Area under curve | 360 ± 70 | 1100 ± 200 | 2400 ± 300 | 5800 ± 700 | 6500 ± 900 | 3800 ± 500 |
Mean residence time, h | 5 ± 1 | 14 ± 2 | 28 ± 4 | 35 ± 6 | 35 ± 4 | 29 ± 3 |
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Zlotnikov, I.D.; Davydova, M.P.; Danilov, M.R.; Krylov, S.S.; Belogurova, N.G.; Kudryashova, E.V. Covalent Conjugates of Allylbenzenes and Terpenoids as Antibiotics Enhancers with the Function of Prolonged Action. Pharmaceuticals 2023, 16, 1102. https://doi.org/10.3390/ph16081102
Zlotnikov ID, Davydova MP, Danilov MR, Krylov SS, Belogurova NG, Kudryashova EV. Covalent Conjugates of Allylbenzenes and Terpenoids as Antibiotics Enhancers with the Function of Prolonged Action. Pharmaceuticals. 2023; 16(8):1102. https://doi.org/10.3390/ph16081102
Chicago/Turabian StyleZlotnikov, Igor D., Maria P. Davydova, Milan R. Danilov, Sergey S. Krylov, Natalya G. Belogurova, and Elena V. Kudryashova. 2023. "Covalent Conjugates of Allylbenzenes and Terpenoids as Antibiotics Enhancers with the Function of Prolonged Action" Pharmaceuticals 16, no. 8: 1102. https://doi.org/10.3390/ph16081102