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Repurposing azithromycin and rifampicin against Gram-negative pathogens by combination with peptide potentiators

Baker, K R; Jana, B; Hansen, A M; Vissing, K J; Nielsen, H M; Franzyk, H; Guardabassi, L

Authors

K R Baker

B Jana

A M Hansen

K J Vissing

H M Nielsen

H Franzyk

L Guardabassi



Abstract

Gram-negative bacterial pathogens are intrinsically resistant to several antibiotics that are not able to penetrate the cell envelope barrier. The aim of this study was to identify peptides that at low concentrations induce susceptibility to these antibiotics in multidrug-resistant (MDR) Gram-negative bacterial strains of clinical relevance. Pairwise screening of 34 diverse peptides and four antibiotics (erythromycin, linezolid, rifampicin and vancomycin) with primary activity against Gram-positive bacteria identified 4 peptides that at submicromolar concentrations conferred susceptibility to rifampicin or erythromycin in Escherichia coli ATCC 25922. The identified peptides exhibited synergy with azithromycin and potentiated clindamycin in MDR E. coli ST131 and Klebsiella pneumoniae ST258. The low cytotoxicity toward eukaryotic cells (IC50 > 50 µM) observed for two of these peptides (KLWKKWKKWLK-NH2 and GKWKKILGKLIR-NH2) prompted synthesis and evaluation of the corresponding all-d analogues (D1 and D2), which retained similar synergistic antibacterial profiles. Low concentrations of D1 and D2 in combination with azithromycin and rifampicin inhibited growth of most clinical E. coli, K. pneumoniae and Acinetobacter baumannii strains tested. These data demonstrate that combinatorial screening at low peptide concentrations constitutes an efficient approach to identify clinically relevant peptide–antibiotic combinations. In vivo pharmacokinetic/pharmacodynamic and toxicity studies are needed to further validate the use of the peptides identified in this study for repurposing azithromycin and rifampicin against Gram-negative pathogens.

Citation

Baker, K. R., Jana, B., Hansen, A. M., Vissing, K. J., Nielsen, H. M., Franzyk, H., & Guardabassi, L. (2018). Repurposing azithromycin and rifampicin against Gram-negative pathogens by combination with peptide potentiators. International Journal of Antimicrobial Agents, 53(6), 868-872. https://doi.org/10.1016/j.ijantimicag.2018.10.025

Journal Article Type Article
Acceptance Date Oct 30, 2018
Publication Date Nov 14, 2018
Deposit Date Jun 6, 2019
Publicly Available Date Mar 28, 2024
Journal INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Print ISSN 0924-8579
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 53
Issue 6
Pages 868-872
DOI https://doi.org/10.1016/j.ijantimicag.2018.10.025
Public URL https://rvc-repository.worktribe.com/output/1385215

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