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

Meirelles, Lucas A. and Perry, Elena K. and Bergkessel, Megan and Newman, Dianne K. (2020) Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200421-132753787

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Abstract

As antibiotic-resistant infections become increasingly prevalent worldwide, understanding the factors that lead to antimicrobial treatment failure is essential to optimizing the use of existing drugs. Opportunistic human pathogens in particular typically exhibit high levels of intrinsic antibiotic resistance and tolerance1, leading to chronic infections that can be nearly impossible to eradicate2. We asked whether the recalcitrance of these organisms to antibiotic treatment could be driven in part by their evolutionary history as environmental microbes, which frequently produce or encounter natural antibiotics3,4. Using the opportunistic pathogen Pseudomonas aeruginosa as a model, we demonstrate that the self-produced natural antibiotic pyocyanin (PYO) activates bacterial defenses that confer collateral tolerance to certain synthetic antibiotics, including in a clinically-relevant growth medium. Non-PYO-producing opportunistic pathogens isolated from lung infections similarly display increased antibiotic tolerance when they are co-cultured with PYO-producing P. aeruginosa. Furthermore, we show that beyond promoting bacterial survival in the presence of antibiotics, PYO can increase the apparent rate of mutation to antibiotic resistance by up to two orders of magnitude. Our work thus suggests that bacterial production of natural antibiotics in infections could play an important role in modulating not only the immediate efficacy of clinical antibiotics, but also the rate at which antibiotic resistance arises in multispecies bacterial communities.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.04.20.049437DOIDiscussion Paper
ORCID:
AuthorORCID
Meirelles, Lucas A.0000-0003-3194-7136
Perry, Elena K.0000-0002-7151-1479
Bergkessel, Megan0000-0002-4530-1224
Newman, Dianne K.0000-0003-1647-1918
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Posted April 20, 2020. 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. Grants to D.K.N. from the NIH (1R01AI127850-01A1) and ARO (W911NF-17-1-0024) supported this work. E.K.P. was supported by a National Science Foundation Graduate Research Fellowship under Grant No. DGE-1745301. Author contributions: These authors contributed equally and are listed alphabetically: Lucas A. Meirelles and Elena K. Perry. Study conception: L.A.M., E.K.P., D.K.N. Study design: L.A.M., E.K.P., M.B., D.K.N. Tn-seq: L.A.M, M.B. Tolerance experiments: L.A.M. Resistance experiments: E.K.P. Manuscript preparation: E.K.P., L.A.M., M.B., D.K.N. Study supervision and funding: D.K.N. The authors declare no competing interests. Data and materials availability: Tn-seq data have been deposited at GEO under accession number GSE148769. Whole genome sequencing data for Δphz and ciprofloxacin-resistant mutants of P. aeruginosa and B. multivorans AU42096 have been deposited at NCBI under accession number PRJNA625945. All other data that support the findings of this study are available from the corresponding author upon reasonable request.
Funders:
Funding AgencyGrant Number
NIH1R01AI127850-01A1
Army Research Office (ARO)W911NF-17-1-0024
NSF Graduate Research FellowshipDGE-1745301
Record Number:CaltechAUTHORS:20200421-132753787
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200421-132753787
Official Citation:Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics. Lucas A Meirelles, Elena K Perry, Megan Bergkessel, Dianne K. Newman. bioRxiv 2020.04.20.049437; doi: https://doi.org/10.1101/2020.04.20.049437
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102703
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Apr 2020 20:42
Last Modified:21 Apr 2020 20:42

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