Document Type
Article
Publication Date
5-2022
Publisher
Oxford University Press
Source Publication
Evolution, Medicine, & Public Health
Source ISSN
2050-6201
Abstract
Background and Objectives
A key strategy for resolving the antibiotic resistance crisis is the development of new drugs with antimicrobial properties. The engineered cationic antimicrobial peptide WLBU2 (also known as PLG0206) is a promising broad-spectrum antimicrobial compound that has completed Phase I clinical studies. It has activity against Gram-negative and Gram-positive bacteria including infections associated with biofilm. No definitive mechanisms of resistance to WLBU2 have been identified.
Methodology
Here, we used experimental evolution under different levels of mutation supply and whole genome sequencing (WGS) to detect the genetic pathways and probable mechanisms of resistance to this peptide. We propagated populations of wild-type and hypermutator Pseudomonas aeruginosa in the presence of WLBU2 and performed WGS of evolved populations and clones.
Results
Populations that survived WLBU2 treatment acquired a minimum of two mutations, making the acquisition of resistance more difficult than for most antibiotics, which can be tolerated by mutation of a single target. Major targets of resistance to WLBU2 included the or fN and pmr B genes, previously described to confer resistance to other cationic peptides. More surprisingly, mutations that increase aggregation such as the wsp pathway were also selected despite the ability of WLBU2 to kill cells growing in a biofilm.
Conclusions and implications
The results show how experimental evolution and WGS can identify genetic targets and actions of new antimicrobial compounds and predict pathways to resistance of new antibiotics in clinical practice.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Santos-Lopez, Alfonso; Fritz, Melissa J.; Lombardo, Jeffrey B.; Burr, Ansen H.P.; Heinrich, Victoria A.; Marshall, Christopher; and Cooper, Vaughn S., "Evolved Resistance to a Novel Cationic Peptide Antibiotic Requires High Mutation Supply" (2022). Biological Sciences Faculty Research and Publications. 909.
https://epublications.marquette.edu/bio_fac/909
Comments
Published version. Evolution, Medicine, and Public Health, Vol. 10, No. 1 (May 2022): 266-276. DOI. © 2022 The Author(s). Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health. Used with permission.
Christopher W. Marshall was affiliated with University of Pittsburgh at the time of publication.