Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Synthesis of MBLIs
Synthesis of BP2
4.2. Bacterial Source
4.3. Drug Susceptibility Testing
4.3.1. Broth Microdilution Assay
4.3.2. Checkerboard Assay
4.3.3. Effects of Human Serum
4.3.4. Time-Kill Study
4.4. Cytotoxicity Assay
4.4.1. Cell Culture
4.4.2. MTT Assay
4.4.3. LDH Assay
4.5. Enzyme Assays
4.5.1. Inhibition of Kinetics
4.5.2. Non-Specific Binding of the Inhibitor to Zinc in Non-MBLs
4.6. Ethical Statement
4.7. In Vivo Efficacy Study
4.8. LC-MS Quantification
4.9. Computational Studies
4.10. Statistical Analyses
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Bacterial Reference | Bacterial Strain | MBL Produced | MIC (mg/L) | FICI | ||
---|---|---|---|---|---|---|
MEM Alone | BP2 Alone | BP2 + MEM | ||||
ATCC 25922 | Escherichia coli | N/A | 0.06 | N/A | 0 + 0.06 | N/A |
AUS 271 | Escherichia coli | NDM-1 | >128 | >256 | 16 + 0.25 | 0.13 |
FEK | Escherichia coli | NDM-4 | >32 | >256 | 16 + 0.5 | 0.07 |
JAP | Escherichia coli | IMP-1 | 8 | >256 | 16 + 0.03 | 0.04 |
TWA | Escherichia coli | IMP-8 | 8 | >256 | 32 + 0.06 | 0.09 |
BM 14 | Escherichia coli | VIM-1 | 32 | >256 | 8 + 0.25 | 0.04 |
TC CARF | Escherichia coli | VIM-2 | 8 | >256 | 4 + 0.5 | 0.08 |
DIH | Escherichia coli | VIM-19 | >32 | >256 | 16 + 0.125 | 0.07 |
IR 386 | Enterobacter cloacae | NDM-1 | 32 | >256 | 16 + 0.125 | 0.07 |
BM 5 | Enterobacter cloacae | IMP-1 | >32 | >256 | 32 + 0.5 | 0.14 |
TWA | Enterobacter cloacae | IMP-8 | 0.125 | >256 | 16 + 0.06 | 0.5 |
KAR | Enterobacter cloacae | VIM-1 | 4 | >256 | 16 + 0.25 | 0.13 |
USA 449 | Klebsiella pneumoniae | NDM | >32 | >256 | 16 + 0.25 | 0.07 |
6852 | Klebsiella pneumoniae | IMP-1 | >32 | >256 | 64 + 1 | 0.3 |
TWA | Klebsiella pneumoniae | IMP-8 | 8 | >256 | 16 + 0.25 | 0.09 |
ENNES | Klebsiella pneumoniae | VIM-1 | >32 | >256 | 8 + 0.5 | 0.05 |
DIH | Klebsiella pneumoniae | VIM-19 | 32 | >256 | 16 + 0.125 | 0.07 |
Serratia marcescens | IMP-11 | >32 | >256 | 64 + 1 | 0.3 | |
BM 20 | Serratia marcescens | VIM-2 | >32 | >256 | 8 + 0.5 | 0.05 |
PSTU | Providencia stuartii | NDM-1 | 32 | >256 | 8 + 0.25 | 0.04 |
IR38 | Providencia Rettgeri | NDM-1 | 32 | >256 | 32 + 0.5 | 0.14 |
MBL | IC50 (µM) | Ki app (µM) |
---|---|---|
NDM-1 | 70.7 ± 4.5 | 35.3 |
VIM-2 | 57.1 ± 2.9 | 30.9 |
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Reddy, N.; Girdhari, L.; Shungube, M.; Gouws, A.C.; Peters, B.K.; Rajbongshi, K.K.; Baijnath, S.; Mdanda, S.; Ntombela, T.; Arumugam, T.; et al. Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors. Antibiotics 2023, 12, 633. https://doi.org/10.3390/antibiotics12040633
Reddy N, Girdhari L, Shungube M, Gouws AC, Peters BK, Rajbongshi KK, Baijnath S, Mdanda S, Ntombela T, Arumugam T, et al. Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors. Antibiotics. 2023; 12(4):633. https://doi.org/10.3390/antibiotics12040633
Chicago/Turabian StyleReddy, Nakita, Letisha Girdhari, Mbongeni Shungube, Arnoldus C. Gouws, Byron K. Peters, Kamal K. Rajbongshi, Sooraj Baijnath, Sipho Mdanda, Thandokuhle Ntombela, Thilona Arumugam, and et al. 2023. "Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors" Antibiotics 12, no. 4: 633. https://doi.org/10.3390/antibiotics12040633
APA StyleReddy, N., Girdhari, L., Shungube, M., Gouws, A. C., Peters, B. K., Rajbongshi, K. K., Baijnath, S., Mdanda, S., Ntombela, T., Arumugam, T., Bester, L. A., Singh, S. D., Chuturgoon, A., Arvidsson, P. I., Maguire, G. E. M., Kruger, H. G., Govender, T., & Naicker, T. (2023). Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors. Antibiotics, 12(4), 633. https://doi.org/10.3390/antibiotics12040633