Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemical Synthesis of AJ-024 and Antibacterial Activity Thereof against Representative C. difficile Strains
2.2. Superior In Vitro Activity of AJ-024 against Extensively Classified C. difficile Clinical Isolates
2.3. Antimicrobial Activities of AJ-024 against Other Bacterial Species
2.4. AJ-024 Has No Appreciable Human Cellular Toxicity
2.5. Favorable ADME Properties of AJ-024
2.6. Time-Kill Assay of AJ-024
2.7. Effect of AJ-024 on Acute CDI In Vivo Infection Model
3. Materials and Methods
3.1. Chemistry
Synthesis of AJ-024
Synthesis of Methyl (2-bromothiazole-4-carbonyl)-L-threoninate (Compound 2)
Synthesis of 2-bromo-N-((2S,3R)-3-hydroxy-1-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)amino)-1-oxobutan-2-yl)thiazole-4-carboxamide (Compound 3)
Synthesis of (Z)-2-bromo-N-(1-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)amino)-1-oxobut-2-en-2-yl)thiazole-4-carboxamide (Compound 4)
Synthesis of ((12Z,32Z,72Z,112Z,4S,8S,12Z,15S)-26-(4-bromothiazol-2-yl)-12-ethylidene-4,15-bis((R)-1-hydroxyethyl)-8-isopropyl-5,9,13,16-tetraaza-1(2,4),3,7,11(4,2) -tetrathiazola-2(3,2)-pyridinacycloheptadecaphane-6,10,14,17-tetraone (AJ-024)
3.2. Cellular Toxicity
3.3. Time-Kill Assays
3.4. In Vivo Bacteria Inoculation
3.5. Mouse IBD-C. difficile Comorbidity Infection Model
3.6. Inhibition of CYP Enzymes Activity by AJ-024
3.7. In Vitro Metabolic Stability of AJ-024
3.8. Plasma Protein Binding Study of AJ-024
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Bacterial Strains | Ribotype | AJ-024 | Vancomycin |
---|---|---|---|
C. difficile ATCC 9689 | 001 | 0.25 | 1 |
C. difficile ATCC 43255 | 087 | 0.25 | 1 |
C. difficile ATCC 51695 | 001 | 0.25 | 1 |
C. difficile ATCC-BAA-1871 | 001 | 0.25 | 1 |
C. difficile ATCC 17858 | 054 | 0.5 | 1 |
Clade | Ribotype | n | MLST | Toxin | VAN | AJ-024 |
---|---|---|---|---|---|---|
1 | RT001 | 3 | ST3 | A+B+ | 2 | 0.5 |
RT002 | 4 | ST8 | A+B+ | 1–2 | 0.25–1 | |
RT012 | 3 | ST54 | A+B+ | 1–2 | 0.25 | |
RT014 | 3 | ST14 | A+B+ | 1 | 0.5 | |
RT015 | 3 | ST35 | A+B+ | 1 | 0.5 | |
RT018 | 10 | ST17 | A+B+ | 0.5–2 | 0.25–1 | |
RT293 | 2 | ST129 | A+B+ | 1 | 0.5–1 | |
2 | RT027 | 3 | ST1 | A+B+CDT+ | 1 | 0.5 |
nt | 1 | ST67 | A+B+CDT+ | 2 | 0.5 | |
3 | RT130 | 5 | ST5 | A+B+CDT+ | 1 | 0.25–1 |
nt | 3 | ST221 | A+B+CDT+ | 1 | 0.25 | |
4 | RT017 | 10 | ST37 | A−B+ | 0.5–1 | 0.25–0.5 |
5 | RT078 | 3 | ST11 | A+B+CDT+ | 1 | 0.25–0.5 |
MIC range | 0.5–2 | 0.25–1 | ||||
MIC50 | 1 | 0.5 |
MIC, μg/mL | |||||
---|---|---|---|---|---|
Gram Positive | Strain | AJ-024 | VAN | LIZ | CIP |
S. aureus | ATCC 25923 | 0.25 | 0.5 | 2 | 0.5 |
S. aureus | ATCC 43300 | 0.25 | 0.5 | 2 | 1 |
S. aureus | Clinical isolate | 0.5 | >32 | 1 | >32 |
E. faecalis | ATCC 29212 | 0.25 | 0.5 | 2 | 1 |
E. faecalis | Clinical isolate | 0.25 | >32 | 4 | >32 |
E. faecium | ATCC 19434 | 0.25 | 1 | 2 | 1 |
E. faecium | Clinical isolate | 0.5 | >32 | 2 | 32 |
Gram Negative | |||||
E. coli | ATCC 25922 | >32 | >32 | >32 | 0.06 |
K. pneumoniae | ATCC 10031 | >32 | >32 | >32 | 0.06 |
P. aeruginosa | ATCC 27853 | >32 | >32 | >32 | 0.5 |
A. baumannii | ATCC 17904 | >32 | >32 | >32 | 0.5 |
CYP Inhibition | PPB | MS | PS | |||||
---|---|---|---|---|---|---|---|---|
1A2 | 2C9 | 2C19 | 2D6 | 3A4 | % Bound | % Remaining (30 min) | % Remaining (30 min) | |
AJ-024 | 68.9 | 73.3 | 57.2 | 77.6 | 62.8 | 99.9 | 63.8 | 95.9 |
Ketoconazole | 94.3 | >100 | 97.6 | >100 | 27.9 | |||
Dexamethasone | 78.8 | |||||||
Warfarin | 98.9 | |||||||
Verapamil | 16.3 | |||||||
Procaine | 1.4 | |||||||
Enalapril | 95.2 |
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Kim, D.; Kim, Y.-R.; Hwang, H.-J.; Ciufolini, M.A.; Lee, J.; Lee, H.; Clovis, S.; Jung, S.; Oh, S.-H.; Son, Y.-J.; et al. Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile. Pharmaceuticals 2022, 15, 623. https://doi.org/10.3390/ph15050623
Kim D, Kim Y-R, Hwang H-J, Ciufolini MA, Lee J, Lee H, Clovis S, Jung S, Oh S-H, Son Y-J, et al. Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile. Pharmaceuticals. 2022; 15(5):623. https://doi.org/10.3390/ph15050623
Chicago/Turabian StyleKim, Dahyun, Young-Rok Kim, Hee-Jong Hwang, Marco A. Ciufolini, Jusuk Lee, Hakyeong Lee, Shyaka Clovis, Sungji Jung, Sang-Hun Oh, Young-Jin Son, and et al. 2022. "Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile" Pharmaceuticals 15, no. 5: 623. https://doi.org/10.3390/ph15050623
APA StyleKim, D., Kim, Y. -R., Hwang, H. -J., Ciufolini, M. A., Lee, J., Lee, H., Clovis, S., Jung, S., Oh, S. -H., Son, Y. -J., & Kwak, J. -H. (2022). Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile. Pharmaceuticals, 15(5), 623. https://doi.org/10.3390/ph15050623