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Phenazines and toxoflavin act as interspecies modulators of resilience to diverse antibiotics

Meirelles, Lucas A. and Newman, Dianne K. (2022) Phenazines and toxoflavin act as interspecies modulators of resilience to diverse antibiotics. Molecular Microbiology, 117 (6). pp. 1384-1404. ISSN 0950-382X. doi:10.1111/mmi.14915.

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Bacterial opportunistic pathogens make diverse secondary metabolites both in the natural environment and when causing infections, yet how these molecules mediate microbial interactions and their consequences for antibiotic treatment are still poorly understood. Here, we explore the role of three redox-active secondary metabolites, pyocyanin, phenazine-1-carboxylic acid, and toxoflavin, as interspecies modulators of antibiotic resilience. We find that these molecules dramatically change susceptibility levels of diverse bacteria to clinical antibiotics. Pyocyanin and phenazine-1-carboxylic acid are made by Pseudomonas aeruginosa, while toxoflavin is made by Burkholderia gladioli, organisms that infect cystic fibrosis and other immunocompromised patients. All molecules alter the susceptibility profile of pathogenic species within the “Burkholderia cepacia complex” to different antibiotics, either antagonizing or potentiating their effects, depending on the drug’s class. Defense responses regulated by the redox-sensitive transcription factor SoxR potentiate the antagonistic effects these metabolites have against fluoroquinolones, and the presence of genes encoding SoxR and the efflux systems it regulates can be used to predict how these metabolites will affect antibiotic susceptibility of different bacteria. Finally, we demonstrate that inclusion of secondary metabolites in standard protocols used to assess antibiotic resistance can dramatically alter the results, motivating the development of new tests for more accurate clinical assessment.

Item Type:Article
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URLURL TypeDescription Paper
Meirelles, Lucas A.0000-0003-3194-7136
Newman, Dianne K.0000-0003-1647-1918
Alternate Title:Redox-active secondary metabolites act as interspecies modulators of antibiotic resilience
Additional Information:© 2022 John Wiley & Sons Ltd. Issue Online: 24 June 2022; Version of Record online: 24 May 2022; Accepted manuscript online: 05 May 2022; Manuscript accepted: 02 May 2022; Manuscript revised: 29 April 2022; Manuscript received: 05 April 2022. We thank Newman lab members for feedback and advice throughout the development of this project. In particular, we thank Megan Bergkessel for assistance and discussions about the RNA-seq, John Ciemniecki for developing and sharing the “dknlab_tools” package used during plate reader data analysis, John LiPuma (University of Michigan, CFF Burkholderia cepacia Research Laboratory and Repository) for providing the clinical Burkholderia strains, and the Microbial Genome Sequencing Center (MiGS) at Pittsburgh for sequencing of the samples. Finally, we thank Jong Ham and Inderjit Barphagha (Louisiana State University) for providing the B. glumae 336gr-1 strains (WT and ∆toxA), and Joanna Goldberg (Emory University) for providing the pEX18Tc plasmid. This work was supported by grants to D.K.N from the NIH (1R01AI127850-01A1, 1R01HL152190-01), and the Doren Family Foundation. Authors' Contributions: Conceptualization, methodology, validation, formal analysis, investigation, data curation, writing—original draft preparation, writing—review & editing, visualization: Lucas A. Meirelles. Conceptualization, resources, writing—review & editing, supervision; project administration; funding acquisition: Dianne K. Newman. The authors declare no competing interests. Usage of Burkholderia gladioli and Burkholderia glumae was permitted by the USDA-APHIS. Data Availability Statement: Data that supports the findings of this study has been deposited at the NCBI Sequence Read Archive under the accession number PRJNA787476.
Funding AgencyGrant Number
Doren Family FoundationUNSPECIFIED
Subject Keywords:antibiotic resistance, antibiotic tolerance, Burkholderia cepacia complex, Burkholderia gladioli, efflux systems, interspecies interactions, polymicrobial infections, Pseudomonas aeruginosa, pyocyanin, toxoflavin
Issue or Number:6
Record Number:CaltechAUTHORS:20211203-174950532
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Official Citation:Meirelles, L. A. & Newman, D. K. (2022). Phenazines and toxoflavin act as interspecies modulators of resilience to diverse antibiotics. Molecular Microbiology, 117, 1384–1404.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112194
Deposited By: George Porter
Deposited On:03 Dec 2021 18:52
Last Modified:30 Jun 2022 17:45

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