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Published March 10, 2021 | Supplemental Material + Submitted + Published
Journal Article Open

Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics


Bacterial opportunistic human pathogens frequently exhibit intrinsic antibiotic tolerance and resistance, resulting in infections that can be nearly impossible to eradicate. We asked whether this recalcitrance could be driven by these organisms' evolutionary history as environmental microbes that engage in chemical warfare. Using Pseudomonas aeruginosa as a model, we demonstrate that the self-produced antibiotic pyocyanin (PYO) activates defenses that confer collateral tolerance specifically to structurally similar synthetic clinical antibiotics. Non-PYO-producing opportunistic pathogens, such as members of the Burkholderia cepacia complex, likewise display elevated antibiotic tolerance when cocultured with PYO-producing strains. Furthermore, by widening the population bottleneck that occurs during antibiotic selection and promoting the establishment of a more diverse range of mutant lineages, PYO increases apparent rates of mutation to antibiotic resistance to a degree that can rival clinically relevant hypermutator strains. Together, these results reveal an overlooked mechanism by which opportunistic pathogens that produce natural toxins can dramatically modulate the efficacy of clinical antibiotics and the evolution of antibiotic resistance, both for themselves and other members of clinically relevant polymicrobial communities.

Additional Information

© 2021 Meirelles et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: December 7, 2020; Accepted: January 4, 2021; Published: March 10, 2021. We thank members of the Newman lab and Shashank Gandhi for constructive feedback throughout the project and on the manuscript. We also thank Steven Wilbert for assistance with image analysis, David Basta for providing the plasmid used for lptA deletion, and The Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech and Igor Antoshechkin for support during library preparation and sequencing of the Tn-seq samples. Finally, we thank John LiPuma (CFF Burkholderia cepacia Research Laboratory and Repository at the University of Michigan) for providing clinical Burkholderia strains and Justin Bois for constructive feedback on our statistical approach. Data Availability: Tn-seq data have been deposited at GEO under accession number GSE148769. Whole genome sequencing data for the parent strains and ciprofloxacin-resistant mutants of P. aeruginosa and B. multivorans AU42096 have been deposited at NCBI under accession number PRJNA625945. All other relevant data are provided within the manuscript and in S1 Data. All strains/plasmids used in this study are available from the corresponding author upon request. Funding: Grants to D.K.N. from the NIH (1R01AI127850-01A1, 1R01HL152190-01), ARO (W911NF-17-1-0024) and the Doren Family Foundation supported this work. E.K.P. was supported by a National Science Foundation Graduate Research Fellowship under Grant No. DGE-1745301. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. Author Contributions: Conceptualization: Lucas A. Meirelles, Elena K. Perry, Dianne K. Newman. Data curation: Lucas A. Meirelles, Elena K. Perry, Megan Bergkessel. Formal analysis: Lucas A. Meirelles, Elena K. Perry, Megan Bergkessel. Funding acquisition: Dianne K. Newman. Investigation: Lucas A. Meirelles, Elena K. Perry, Megan Bergkessel. Methodology: Lucas A. Meirelles, Elena K. Perry, Megan Bergkessel. Project administration: Lucas A. Meirelles, Elena K. Perry, Dianne K. Newman. Resources: Dianne K. Newman. Supervision: Dianne K. Newman. Validation: Lucas A. Meirelles, Elena K. Perry. Visualization: Lucas A. Meirelles, Elena K. Perry, Megan Bergkessel. Writing – original draft: Lucas A. Meirelles, Elena K. Perry, Megan Bergkessel, Dianne K. Newman. Writing – review & editing: Lucas A. Meirelles, Elena K. Perry, Dianne K. Newman.

Attached Files

Published - journal.pbio.3001093.pdf

Submitted - 2020.04.20.049437v1.full.pdf

Supplemental Material - journal.pbio.3001093.s001.tif

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Supplemental Material - journal.pbio.3001093.s016.xlsx

Supplemental Material - journal.pbio.3001093.s017.mp4

Supplemental Material - journal.pbio.3001093.s018.zip


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August 20, 2023
December 22, 2023