Reverting Antibiotic Tolerance of Pseudomonas aeruginosa PAO1 Persister Cells by (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one

Pan, Jiachuan; Bahar, Ali Adem; Syed, Haseeba; Ren, Dacheng

doi:10.1371/journal.pone.0045778

Cited by 67 publications

(52 citation statements)

References 42 publications

(62 reference statements)

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“…Persister cells were isolated through SOS response selection upon exposure to ciprofloxacin. The use of ciprofloxacin or ampicillin is the main standardized procedure for persister cell isolation and has been widely used in previous studies (2,4,14,19,29,30,44). To ensure adequate isolation of persister cell populations from P. aeruginosa biofilms, we used E. coli cultures as a control, where persister cell isolation from both planktonic and biofilm populations is well documented (2,4,14,19,29,30,44).…”

Section: Resultsmentioning

confidence: 99%

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The Fatty Acid Signaling Molecule cis -2-Decenoic Acid Increases Metabolic Activity and Reverts Persister Cells to an Antimicrobial-Susceptible State

Marques

Morozov

Planzos

et al. 2014

Appl Environ Microbiol

122

112

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bPersister cells, which are tolerant to antimicrobials, contribute to biofilm recalcitrance to therapeutic agents. In turn, the ability to kill persister cells is believed to significantly improve efforts in eradicating biofilm-related, chronic infections. While much research has focused on elucidating the mechanism(s) by which persister cells form, little is known about the mechanism or factors that enable persister cells to revert to an active and susceptible state. Here, we demonstrate that cis-2-decenoic acid (cis-DA), a fatty acid signaling molecule, is able to change the status of Pseudomonas aeruginosa and Escherichia coli persister cells from a dormant to a metabolically active state without an increase in cell number. This cell awakening is supported by an increase of the persister cells' respiratory activity together with changes in protein abundance and increases of the transcript expression levels of several metabolic markers, including acpP, 16S rRNA, atpH, and ppx. Given that most antimicrobials target actively growing cells, we also explored the effect of cis-DA on enhancing antibiotic efficacy in killing persister cells due to their inability to keep a persister cell state. Compared to antimicrobial treatment alone, combinational treatments of persister cell subpopulations with antimicrobials and cis-DA resulted in a significantly greater decrease in cell viability. In addition, the presence of cis-DA led to a decrease in the number of persister cells isolated. We thus demonstrate the ability of a fatty acid signaling molecule to revert bacterial cells from a tolerant phenotype to a metabolically active, antimicrobial-sensitive state. P ersister cells are considered to be a subpopulation of stochastically produced, nongrowing (dormant) cells present in biofilm and planktonic bacterial cultures. Persister cells account for 10 Ϫ6 to 10 Ϫ4 of the total cell population of mid-exponential-phase cells and up to 1% of the total cell population of stationary-phase cells and biofilms, a pattern resembling that of a quorum-sensing mechanism (1-3). Tolerance to antimicrobials is one of the key characteristics of this subpopulation, as persisters escape killing by antimicrobials such as fluoroquinolones, which can kill slowgrowing bacteria but not dormant cells (4). It is therefore not surprising that persister cells are considered to play a major role in the resilience of bacterial populations and have recently been isolated from patients with candidiasis, from cystic fibrosis patients with chronic lung infections, and from Mycobacterium tuberculosis biofilms responsible for chronic tuberculosis (5-8).Several mechanisms have been described to contribute to persister cell formation. For instance, several genes involved in energy generation and cell maintenance have been shown to be downregulated in persister cells, further indicating that persisters are nongrowing, dormant cells (1). Among these genes were members of several operons involved in oxidative phosphorylation, including NADH dehydrogenase, ATP syn...

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Section: Resultsmentioning

confidence: 99%

“…Likewise, the addition of the quorum sensing inhibitor (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one (BF8) to Pseudomonas aeruginosa persister cells has been shown to sensitize them to ciprofloxacin and tobramycin, with the effect hypothesized to be the result of changes in the cells' metabolism (19).…”

mentioning

confidence: 99%

The Fatty Acid Signaling Molecule cis -2-Decenoic Acid Increases Metabolic Activity and Reverts Persister Cells to an Antimicrobial-Susceptible State

Marques

Morozov

Planzos

et al. 2014

Appl Environ Microbiol

122

112

View full text Add to dashboard Cite

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“…Treatment of isolated persister cells. Persister cells were isolated as described previously, with minor modifications (57). Stationary-phase cells were treated with ofloxacin (10 g/ml) for 5 h. Higher ofloxacin concentrations or increased incubation times did not lead to a further reduction of the number of surviving cells (data not shown).…”

Section: Methodsmentioning

confidence: 98%

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Liebens

Defraine

Knapen

et al. 2017

Antimicrob Agents Chemother

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Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen to be a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current study focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and, due to increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of P. aeruginosa infections is the presence of persister cells, and elimination of these cells would therefore significantly improve patient outcomes. In this study, a smallmolecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of P. aeruginosa persisters compared to the number achieved with treatment with the antibiotic alone. Based on the early structure-activity relationship, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 10 6 -fold in both lab strains and clinical isolates of P. aeruginosa. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. In conclusion, we identified a novel antipersister compound active against P. aeruginosa with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections.

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“…However, the mechanism was not determined. Also, Pan et al (53) found a new use for brominated furanones that have been studied for inhibiting quorum sensing by finding that (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one wakes P. aeruginosa planktonic and biofilm persister cells. They also determined that the compound is effective with mucoid P. aeruginosa (54).…”

Section: Preventing Persistence and Waking Persistersmentioning

confidence: 99%

Bacterial Persister Cell Formation and Dormancy

Wood

Knabel

Kwan

2013

Appl Environ Microbiol

550

432

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Bacterial cells may escape the effects of antibiotics without undergoing genetic change; these cells are known as persisters. Unlike resistant cells that grow in the presence of antibiotics, persister cells do not grow in the presence of antibiotics. These persister cells are a small fraction of exponentially growing cells (due to carryover from the inoculum) but become a significant fraction in the stationary phase and in biofilms (up to 1%). Critically, persister cells may be a major cause of chronic infections. The mechanism of persister cell formation is not well understood, and even the metabolic state of these cells is debated. Here, we review studies relevant to the formation of persister cells and their metabolic state and conclude that the best model for persister cells is still dormancy, with the latest mechanistic studies shedding light on how cells reach this dormant state.

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Reverting Antibiotic Tolerance of Pseudomonas aeruginosa PAO1 Persister Cells by (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one

Cited by 67 publications

References 42 publications

The Fatty Acid Signaling Molecule cis -2-Decenoic Acid Increases Metabolic Activity and Reverts Persister Cells to an Antimicrobial-Susceptible State

The Fatty Acid Signaling Molecule cis -2-Decenoic Acid Increases Metabolic Activity and Reverts Persister Cells to an Antimicrobial-Susceptible State

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Bacterial Persister Cell Formation and Dormancy

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