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Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance

Marrs, Emma C.L., Varadi, Linda, Bedernjak, Alexandre F., Day, Kathryn M., Gray, Mark, Jones, Amanda L., Cummings, Stephen P., Anderson, Rosaleen and Perry, John D. (2020) Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance. Molecules, 25 (6). e1445. ISSN 1420-3049

Item Type: Article


Given the increase in resistance to antibacterial agents, there is an urgent need for the development of new agents with novel modes of action. As an interim solution, it is also prudent to reinvestigate old or abandoned antibacterial compounds to assess their efficacy in the context of widespread resistance to conventional agents. In the 1970s, much work was performed on the development of peptide mimetics, exemplified by the phosphonopeptide, alafosfalin. We investigated the activity of alafosfalin, di-alanyl fosfalin and β-chloro-L-alanyl-β-chloro-L-alanine against 297 bacterial isolates, including carbapenemase-producing Enterobacterales (CPE) (n = 128), methicillin-resistant Staphylococcus aureus (MRSA) (n = 37) and glycopeptide-resistant enterococci (GRE) (n = 43). The interaction of alafosfalin with meropenem was also examined against 20 isolates of CPE. The MIC50 and MIC90 of alafosfalin for CPE were 1 mg/L and 4 mg/L, respectively and alafosfalin acted synergistically when combined with meropenem against 16 of 20 isolates of CPE. Di-alanyl fosfalin showed potent activity against glycopeptide-resistant isolates of Enterococcus faecalis (MIC90; 0.5 mg/L) and Enterococcus faecium (MIC90; 2 mg/L). Alafosfalin was only moderately active against MRSA (MIC90; 8 mg/L), whereas β-chloro-L-alanyl-β-chloro-L-alanine was slightly more active (MIC90; 4 mg/L). This study shows that phosphonopeptides, including alafosfalin, may have a therapeutic role to play in an era of increasing antibacterial resistance.

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Additional Information: ** From MDPI via Jisc Publications Router ** History: accepted 20-03-2020; pub-electronic 23-03-2020. ** Licence for this article:
Uncontrolled Keywords: phosphonopeptides, alafosfalin, carbapenemase, antimicrobial resistance, glycopeptide-resistant enterococci, MRSA
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Item ID: 11875
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ISSN: 1420-3049

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ORCID for Linda Varadi: ORCID iD
ORCID for Mark Gray: ORCID iD
ORCID for John D. Perry: ORCID iD

Catalogue record

Date Deposited: 25 Mar 2020 08:24
Last Modified: 30 Sep 2020 10:46


Author: Linda Varadi ORCID iD
Author: Mark Gray ORCID iD
Author: John D. Perry ORCID iD
Author: Emma C.L. Marrs
Author: Alexandre F. Bedernjak
Author: Kathryn M. Day
Author: Amanda L. Jones
Author: Stephen P. Cummings
Author: Rosaleen Anderson

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Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences

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