Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Antibacterial Agents and Media
4.2. Bacterial Isolates
4.3. Determination of MICs
4.4. Study of the Interaction between Alafosfalin and Meropenem Against Carbapenemase-Producing Enterobacterales
5. Concluding Remarks
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: If not available from a commercial source, samples of the compounds are available from the authors. |
Organism (No. Tested) and Antimicrobial Agent | Concentration (mg/L) | |||
---|---|---|---|---|
Mode | MIC50 | MIC90 | Range | |
Enterobacterales (n = 197) | ||||
Alafosfalin | 2 | 2 | > 8 | ≤0.031–>8 |
Di-alanyl fosfalin | > 8 | 8 | > 8 | ≤ 0.031–> 8 |
β-Cl-Ala-β-Cl-Ala | > 8 | > 8 | > 8 | 2–> 8 |
Fosfomycin | 4 | 4 | > 32 | 0.125–> 32 |
E. coli (n = 53) | ||||
Alafosfalin | 0.063 | 0.125 | 0.25 | ≤ 0.031–2 |
Di-alanyl fosfalin | 0.25 | 0.5 | 2 | ≤ 0.031–> 8 |
β-Cl-Ala-β-Cl-Ala | 8 | 8 | > 8 | 2–> 8 |
Fosfomycin | 0.5 | 0.5 | 1 | 0.125–8 |
K. pneumoniae (n = 87) | ||||
Alafosfalin | 2 | 2 | > 8 | 0.25–> 8 |
Di-alanyl fosfalin | > 8 | > 8 | > 8 | 0.5–> 8 |
β-Cl-Ala-β-Cl-Ala | > 8 | > 8 | > 8 | 8–> 8 |
Fosfomycin | 4 | 8 | > 32 | 2–> 32 |
E. cloacae (n = 27) | ||||
Alafosfalin | 1 | 1 | 1 | 0.125–4 |
Di-alanyl fosfalin | 4 | > 8 | > 8 | 0.25–> 8 |
β-Cl-Ala-β-Cl-Ala | > 8 | > 8 | > 8 | 8–> 8 |
Fosfomycin | 16 | 16 | 32 | 4–> 32 |
CPE (n = 128) | ||||
Alafosfalin | 2 | 1 | 4 | ≤ 0.031–> 8 |
Di-alanyl fosfalin | > 8 | 8 | > 8 | 0.063–> 8 |
β-Cl-Ala-β-Cl-Ala | > 8 | > 8 | > 8 | 2–> 8 |
Fosfomycin | 16 | 4 | 32 | 0.125–> 32 |
ESBL (n = 47) | ||||
Alafosfalin | 2 | 2 | > 8 | ≤ 0.031–> 8 |
Di-alanyl fosfalin | > 8 | 8 | > 8 | ≤ 0.031–> 8 |
β-Cl-Ala-β-Cl-Ala | > 8 | > 8 | > 8 | 2–> 8 |
Fosfomycin | > 32 | 8 | > 32 | 0.125–> 32 |
AmpC (n = 22) | ||||
Alafosfalin | > 8 | 4 | > 8 | 0.063–> 8 |
Di-alanyl fosfalin | > 8 | > 8 | > 8 | 0.063–> 8 |
β-Cl-Ala-β-Cl-Ala | > 8 | > 8 | > 8 | 8–> 8 |
Fosfomycin | 32 | 8 | > 32 | 0.125–> 32 |
Organism (No. Tested) and Antimicrobial Agent | Concentration (mg/L) | |||
---|---|---|---|---|
Mode | MIC50 | MIC90 | Range | |
All S. aureus (n = 50) | ||||
Alafosfalin | 4 | 4 | 8 | 0.125–16 |
Di-alanyl fosfalin | 4 | 8 | 16 | 0.5–32 |
β-Cl-Ala-β-Cl-Ala | 2 | 2 | 4 | 0.125–16 |
Fosfomycin | 8 | 4 | 16 | 0.5–> 32 |
MRSA (n = 37) | ||||
Alafosfalin | 4 | 4 | 8 | 0.125–16 |
Di-alanyl fosfalin | 4 | 8 | 16 | 0.5–32 |
β-Cl-Ala-β-Cl-Ala | 2 | 2 | 4 | 0.125–16 |
Fosfomycin | 8 | 4 | 16 | 0.5–> 32 |
MSSA (n = 13) | ||||
Alafosfalin | 4 | 4 | 8 | 0.25–16 |
Di-alanyl fosfalin | 16 | 8 | 16 | 0.5–32 |
β-Cl-Ala-β-Cl-Ala | 1 | 1 | 2 | 0.5–2 |
Fosfomycin | 4 | 4 | 16 | 2–16 |
All Enterococci (n = 50) | ||||
Alafosfalin | 8 | 16 | > 32 | 4–> 32 |
Di-alanyl fosfalin | 0.5 | 0.5 | 2 | ≤ 0.016–> 32 |
β-Cl-Ala-β-Cl-Ala | 16 | 16 | 32 | 2–16 |
Fosfomycin | > 32 | > 32 | > 32 | 16–> 32 |
E. faecalis (n = 11) | ||||
Alafosfalin | 8 | 8 | 32 | 4–> 32 |
Di-alanyl fosfalin | 0.031 | 0.063 | 0.5 | ≤ 0.016–> 32 |
β-Cl-Ala-β-Cl-Ala | 8 | 8 | 16 | 4–16 |
Fosfomycin | 32 | 32 | > 32 | 32–> 32 |
E. faecium (n = 34) | ||||
Alafosfalin | 16 | 16 | 16 | 4–32 |
Di-alanyl fosfalin | 0.5 | 0.5 | 2 | ≤ 0.016–4 |
β-Cl-Ala-β-Cl-Ala | 16 | 16 | 32 | 2–> 32 |
Fosfomycin | > 32 | > 32 | > 32 | 16–> 32 |
GRE (n = 43) | ||||
Alafosfalin | 16 | 16 | > 32 | 4–> 32 |
Di-alanyl fosfalin | 0.5 | 0.5 | > 32 | ≤ 0.016–> 32 |
β-Cl-Ala-β-Cl-Ala | 16 | 16 | > 32 | 4–> 32 |
Fosfomycin | > 32 | > 32 | > 32 | 32–> 32 |
Species | Carbapenemase | Alafosfalin MIC (mg/L) | Meropenem MIC (mg/L) | FICI | Interpretation |
---|---|---|---|---|---|
K. oxytoca | KPC-2 | 4 | 0.25 | 0.16 | Synergy |
K. pneumoniae | KPC-3 | 1 | 1 | 0.25 | Synergy |
K. pneumoniae | KPC-3 | 1 | 16 | 0.19 | Synergy |
K. pneumoniae | KPC-4 | 0.5 | 4 | 0.38 | Synergy |
K. pneumoniae | KPC | 1 | 0.25 | 0.38 | Synergy |
E. coli | NDM-1 | 0.125 | 8 | 0.75 | No interaction |
E. coli | NDM-1 | 0.031 | 0.125 | 0.76 | No interaction |
E. cloacae | NDM-1 | 1 | 4 | 1 | No interaction |
K. pneumoniae | NDM-1 | 2 | 2 | 0.27 | Synergy |
E. coli | NDM-1 | 0.125 | 16 | 0.25 | Synergy |
E. cloacae | VIM-1 | 2 | 4 | 0.19 | Synergy |
K. pneumoniae | VIM-1 | 2 | 16 | 0.28 | Synergy |
K. pneumoniae | IMP | 0.25 | 1 | 0.37 | Synergy |
K. pneumoniae | IMP | 0.25 | 1 | 0.50 | Synergy |
K. oxytoca | IMP | 1 | 0.5 | 0.13 | Synergy |
K. pneumoniae | OXA-48 | 1 | 8 | 0.38 | Synergy |
E. coli | OXA-48 | 0.125 | 0.25 | 0.37 | Synergy |
K. pneumoniae | OXA-48 | 2 | 1 | 0.5 | Synergy |
K. pneumoniae | OXA-48 | 2 | 4 | 0.26 | Synergy |
K. pneumoniae | OXA-48 | 1 | 2 | 0.63 | No interaction |
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Marrs, E.C.L.; Varadi, L.; Bedernjak, A.F.; Day, K.M.; Gray, M.; Jones, A.L.; Cummings, S.P.; Anderson, R.J.; Perry, J.D. Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance. Molecules 2020, 25, 1445. https://doi.org/10.3390/molecules25061445
Marrs ECL, Varadi L, Bedernjak AF, Day KM, Gray M, Jones AL, Cummings SP, Anderson RJ, Perry JD. Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance. Molecules. 2020; 25(6):1445. https://doi.org/10.3390/molecules25061445
Chicago/Turabian StyleMarrs, Emma C.L., Linda Varadi, Alexandre F. Bedernjak, Kathryn M. Day, Mark Gray, Amanda L. Jones, Stephen P. Cummings, Rosaleen J. Anderson, and John D. Perry. 2020. "Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance" Molecules 25, no. 6: 1445. https://doi.org/10.3390/molecules25061445