Associated Faculty, Chemical and Biological Engineering

Contact

mbrynild@Princeton.EDU
609-258-1995
Hoyt Chemical Laboratory, 205
Brynildsen Lab

Research Area

Microbiology & Virology

Research Focus

Bacterial persistence and host-pathogen interactions



Research
Selected Publications
With the ever-increasing incidence of antibiotic-resistant infections and a weak pipeline of new antibiotics, our antibiotic arsenal is in danger of becoming obsolete. Since conventional antibiotic discovery is failing to keep pace with the rise of resistance, fresh perspectives and novel methodologies are needed to address this critical public health issue. The main focus of our group is to use both computational and experimental techniques in systems biology, synthetic biology, and metabolic engineering to understand and combat infectious disease. We focus on two key areas: host-pathogen interactions and bacterial persistence.

Host-pathogen interactions

The increase in the frequency of antibiotic-resistant strains has researchers searching for new antimicrobials or novel ways to potentiate current therapeutics. One exciting approach with great potential is antivirulence therapy, which focuses on disrupting the ability of a pathogen to infect a host. Rather than targeting essential bacterial functions as current antibiotics do, antivirulence therapy targets essential host-pathogen interactions required for infection such as adhesion, quorum sensing, and susceptibility to immune attack. These therapies are less prone to resistance development due to their ability to provide selective pressure only within the host, and have the potential to greatly expand our antimicrobial capabilities. In this area, we aim to leverage our knowledge and understanding of bacterial metabolism to increase the susceptibility of pathogens to killing by various immune antimicrobials, including reactive oxygen species, reactive nitrogen species, and antimicrobial peptides.

Bacterial persistence

Bacterial persistence is a non-genetic, non-inherited (epigenetic) ability in bacteria to tolerate antibiotics and other stress. This distinct physiological state is thought to cause chronic and recurrent infection, and represents an insurance policy in which a small portion of cells enter dormancy and sacrifice their ability to replicate in order to survive stress at a future time. The proportion of persisters in a population varies by strain and environment (generally 1 in 100 to 1 in 1,000,000 cells), and the mechanism of persister formation as well as the content of their physiology remain elusive. A major goal of our group is the reconstruction of persister physiology using systems biology to identify active portions of their metabolic, signal transduction, and transcriptional regulatory networks. This work will provide the first cellular-level persister network and direct efforts to eliminate persisters as a source of chronic infection.




Wan X, A Link J, Brynildsen MP. Translational Fusion to Hmp Improves Heterologous Protein Expression. Microorganisms. 2022 ;10(2). PubMed
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Lemma AS, Soto-Echevarria N, Brynildsen MP. Fluoroquinolone Persistence in Requires DNA Repair despite Differing between Starving Populations. Microorganisms. 2022 ;10(2). PubMed
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Sivaloganathan DM, Brynildsen MP. Pseudomonas aeruginosa prioritizes detoxification of hydrogen peroxide over nitric oxide. BMC Res Notes. 2021 ;14(1):120. PubMed
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Wan X, Brynildsen MP. Robustness of nitric oxide detoxification to nitrogen starvation in Escherichia coli requires RelA. Free Radic Biol Med. 2021 ;176:286-297. PubMed
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Adams RA, Leon G, Miller NM, Reyes SP, Thantrong CH, Thokkadam AM, et al. Rifamycin antibiotics and the mechanisms of their failure. J Antibiot (Tokyo). 2021 ;74(11):786-798. PubMed
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Lemma AS, Brynildsen MP. Toxin Induction or Inhibition of Transcription or Translation Posttreatment Increases Persistence to Fluoroquinolones. mBio. 2021 ;12(4):e0198321. PubMed
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Sivaloganathan DM, Brynildsen MP. Phagosome-Bacteria Interactions from the Bottom Up. Annu Rev Chem Biomol Eng. 2021 ;12:309-331. PubMed
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Murawski AM, Brynildsen MP. Ploidy is an important determinant of fluoroquinolone persister survival. Curr Biol. 2021 ;31(10):2039-2050.e7. PubMed
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Aedo SJ, Tang J, Brynildsen MP. Metabolites Potentiate Nitrofurans in Nongrowing Escherichia coli. Antimicrob Agents Chemother. 2021 ;65(3). PubMed
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Murawski AM, Rittenbach K, DeCoste CJ, Laevsky G, Brynildsen MP. Counting Chromosomes in Individual Bacteria to Quantify Their Impacts on Persistence. Methods Mol Biol. 2021 ;2357:125-146. PubMed
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Sivaloganathan DM, Wan X, Brynildsen MP. Quantifying Nitric Oxide Flux Distributions. Methods Mol Biol. 2020 ;2088:161-188. PubMed
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Sivaloganathan DM, Brynildsen MP. Quantitative Modeling Extends the Antibacterial Activity of Nitric Oxide. Front Physiol. 2020 ;11:330. PubMed
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Chou WKang, Vaikunthan M, Schr?der HV, A Link J, Kim H, Brynildsen MP. Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide. Front Bioeng Biotechnol. 2020 ;8:1001. PubMed
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Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B, Andersson DI, et al. Publisher Correction: Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol. 2019 ;17(7):460. PubMed
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Adolfsen KJ, Chou WKang, Brynildsen MP. Transcriptional Regulation Contributes to Prioritized Detoxification of Hydrogen Peroxide over Nitric Oxide. J Bacteriol. 2019 ;201(14). PubMed
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Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B, Andersson DI, et al. Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol. 2019 ;17(7):441-448. PubMed
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Aedo SJ, Orman MA, Brynildsen MP. Stationary phase persister formation in Escherichia coli can be suppressed by piperacillin and PBP3 inhibition. BMC Microbiol. 2019 ;19(1):140. PubMed
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Barrett TC, Mok WWK, Murawski AM, Brynildsen MP. Enhanced antibiotic resistance development from fluoroquinolone persisters after a single exposure to antibiotic. Nat Commun. 2019 ;10(1):1177. PubMed
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Chou WKang, Brynildsen MP. Loss of DksA leads to multi-faceted impairment of nitric oxide detoxification by Escherichia coli. Free Radic Biol Med. 2019 ;130:288-296. PubMed
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Aedo SJ, Ma HR, Brynildsen MP. Checks and Balances with Use of the Keio Collection for Phenotype Testing. Methods Mol Biol. 2019 ;1927:125-138. PubMed
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Gowers G-OF, Robinson JL, Brynildsen MP. Corrigendum to "Starved Escherichia coli preserve reducing power under nitric oxide stress" Biochemical and Biophysical Research Communications, Volume 476, Issue 115, July 2016, Pages 29-34. Biochem Biophys Res Commun. 2018 ;505(2):631. PubMed
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Mok WWK, Brynildsen MP. Timing of DNA damage responses impacts persistence to fluoroquinolones. Proc Natl Acad Sci U S A. 2018 ;115(27):E6301-E6309. PubMed
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Brynildsen MP. Nitric Oxide Stress as a Metabolic Flux. Adv Microb Physiol. 2018 ;73:63-76. PubMed
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Mok WWK, Brynildsen MP. An Orphan Riboswitch Unveils Guanidine Regulation in Bacteria. Mol Cell. 2017 ;65(2):205-206. PubMed
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Sacco SA, Adolfsen KJ, Brynildsen MP. An integrated network analysis identifies how ArcAB enables metabolic oscillations in the nitric oxide detoxification network of Escherichia coli. Biotechnol J. 2017 ;12(8). PubMed
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Aedo SJ, Gelderman G, Brynildsen MP. Tackling host-circuit give and take. Nat Microbiol. 2017 ;2(12):1584-1585. PubMed
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Robinson JL, Jaslove JM, Murawski AM, Fazen CH, Brynildsen MP. An integrated network analysis reveals that nitric oxide reductase prevents metabolic cycling of nitric oxide by Pseudomonas aeruginosa. Metab Eng. 2017 ;41:67-81. PubMed
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Barrett TC, Mok WWK, Brynildsen MP. Biased inheritance protects older bacteria from harm. Science. 2017 ;356(6335):247-248. PubMed
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Henry TC, Brynildsen MP. Quantifying Current Events Identifies a Novel Endurance Regulator. Trends Microbiol. 2016 ;24(5):324-326. PubMed
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Robinson JL, Brynildsen MP. Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network of Escherichia coli. Proc Natl Acad Sci U S A. 2016 ;113(12):E1757-66. PubMed
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Orman MA, Brynildsen MP. Persister formation in Escherichia coli can be inhibited by treatment with nitric oxide. Free Radic Biol Med. 2016 ;93:145-54. PubMed
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Gowers G-OF, Robinson JL, Brynildsen MP. Starved Escherichia coli preserve reducing power under nitric oxide stress. Biochem Biophys Res Commun. 2016 ;476(1):29-34. PubMed
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Hoegler KJ, Hecht MH. A de novo protein confers copper resistance in Escherichia coli. Protein Sci. 2016 ;25(7):1249-59. PubMed
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Henry TC, Brynildsen MP. Development of Persister-FACSeq: a method to massively parallelize quantification of persister physiology and its heterogeneity. Sci Rep. 2016 ;6:25100. PubMed
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Orman MA, Henry TC, DeCoste CJ, Brynildsen MP. Analyzing Persister Physiology with Fluorescence-Activated Cell Sorting. Methods Mol Biol. 2016 ;1333:83-100. PubMed
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V?lzing KG, Brynildsen MP. Stationary-Phase Persisters to Ofloxacin Sustain DNA Damage and Require Repair Systems Only during Recovery. mBio. 2015 ;6(5):e00731-15. PubMed
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Robinson JL, Brynildsen MP. An ensemble-guided approach identifies ClpP as a major regulator of transcript levels in nitric oxide-stressed Escherichia coli. Metab Eng. 2015 ;31:22-34. PubMed
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Sandvik EL, Fazen CH, Henry TC, Mok WWK, Brynildsen MP. Non-Monotonic Survival of Staphylococcus aureus with Respect to Ciprofloxacin Concentration Arises from Prophage-Dependent Killing of Persisters. Pharmaceuticals (Basel). 2015 ;8(4):778-92. PubMed
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Mok WWK, Park JO, Rabinowitz JD, Brynildsen MP. RNA Futile Cycling in Model Persisters Derived from MazF Accumulation. mBio. 2015 ;6(6):e01588-15. PubMed
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Adolfsen KJ, Brynildsen MP. A Kinetic Platform to Determine the Fate of Hydrogen Peroxide in Escherichia coli. PLoS Comput Biol. 2015 ;11(11):e1004562. PubMed
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Orman MA, Mok WWK, Brynildsen MP. Aminoglycoside-enabled elucidation of bacterial persister metabolism. Curr Protoc Microbiol. 2015 ;36:17.9.1-17.9.14. PubMed
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Amato SM, Brynildsen MP. Persister Heterogeneity Arising from a Single Metabolic Stress. Curr Biol. 2015 ;25(16):2090-8. PubMed
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Orman MA, Brynildsen MP. Inhibition of stationary phase respiration impairs persister formation in E. coli. Nat Commun. 2015 ;6:7983. PubMed
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