Document Type

Article

Publication Date

2024

DOI

10.1371/journal.pone.0295627

Publication Title

PLoS One

Volume

19

Issue

1

Pages

e0295627 (1-25)

Abstract

The spore-forming intestinal pathogen Clostridioides difficile causes multidrug resistant infection with a high rate of recurrence after treatment. Piscidins 1 (p1) and 3 (p3), cationic host defense peptides with micromolar cytotoxicity against C. difficile, sensitize C. difficile to clinically relevant antibiotics tested at sublethal concentrations. Both peptides bind to Cu2+ using an amino terminal copper and nickel binding motif. Here, we investigate the two peptides in the apo and holo states as antibiotic adjuvants against an epidemic strain of C. difficile. We find that the presence of the peptides leads to lower doses of metronidazole, vancomycin, and fidaxomicin to kill C. difficile. The activity of metronidazole, which targets DNA, is enhanced by a factor of 32 when combined with p3, previously shown to bind and condense DNA. Conversely, the activity of vancomycin, which acts at bacterial cell walls, is enhanced 64-fold when combined with membrane-active p1-Cu2+. As shown through microscopy monitoring the permeabilization of membranes of C. difficile cells and vesicle mimics of their membranes, the adjuvant effect of p1 and p3 in the apo and holo states is consistent with a mechanism of action where the peptides enable greater antibiotic penetration through the cell membrane to increase their bioavailability. The variations in effects obtained with the different forms of the peptides reveal that while all piscidins generally sensitize C. difficile to antibiotics, co-treatments can be optimized in accordance with the underlying mechanism of action of the peptides and antibiotics. Overall, this study highlights the potential of antimicrobial peptides as antibiotic adjuvants to increase the lethality of currently approved antibiotic dosages, reducing the risk of incomplete treatments and ensuing drug resistance.

Rights

© 2024 Oludiran et al.

This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability

Article states: "All relevant data are within the manuscript and its Supporting Information files."

Original Publication Citation

Oludiran, A., Malik, A., Zourou, A. C., Wu, Y., Gross, S. P., Siryapon, A., Poudel, A., Alleyne, K., Adams, S., Courson, D. S., Cotten, M. L., & Purcell, E. B. (2024). Host-defense piscidin peptides as antibiotic adjuvants against Clostridioides difficile. PloS ONE, 19(1), 1-25, Article e0295627. https://doi.org/10.1371/journal.pone.0295627

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