Extracellular DNA Promotes Efficient Extracellular Electron Transfer by Pyocyanin in Pseudomonas aeruginosa Biofilms

Saunders, Scott H.; Tse, Edmund C. M.; Yates, Matthew D.; Otero, Fernanda Jiménez; Trammell, Scott A.; Stemp, Eric D. A.; Barton, Jacqueline K.; Tender, Leonard M.; Newman, Dianne K.

doi:10.1016/j.cell.2020.07.006

Cited by 184 publications

(97 citation statements)

References 81 publications

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“…Alternatively, the observed increased tolerance to tobramycin in that study might not be related to molecular defenses induced by phenazines, but rather phenazine-mediated physiological differences under the studied conditions [ 17 ]. Phenazines are redox-active molecules that can promote metabolic activity under oxygen limitation, which occurs within biofilms [ 12 , 17 , 69 ]; the specific details of how such metabolic activity might affect antibiotic tolerance merit further attention. The other previous study found that PYO increased planktonic culture cell densities in the presence of various antibiotics [ 18 ], but these experiments did not directly demonstrate an effect on antibiotic tolerance (i.e., the ability to survive an otherwise lethal antibiotic treatment) [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

“…P. aeruginosa produces several redox-active, heterocyclic compounds known as phenazines [10]. Phenazines have been shown to provide multiple benefits for their producers, including by (i) serving as an alternative electron acceptor in the absence of oxygen, thereby promoting redox homeostasis and anaerobic survival [11], which is particularly relevant for oxidant-limited biofilms [12]; (ii) acting as signaling molecules [13]; (iii) promoting iron acquisition [14]; and (iv) killing competitor species [15]. In addition, despite possessing broad-spectrum antimicrobial activity [10], including against P. aeruginosa itself [16], phenazines have recently been shown to promote tolerance to clinical antibiotics under some circumstances, via mechanisms that have yet to be characterized [17,18].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Bacteria are usually embedded in a self-produced matrix to form biofilm, and the complex architecture of a biofilm is maintained by an extracellular matrix of EPSs, proteins, and eDNA ( Flemming and Wingender, 2010 ; Candela et al, 2019 ). The function of eDNA in biofilms has attracted much attention in recent years ( Okshevsky et al, 2015 ; Saunders et al, 2020 ). Bacillus cereus follows this rule, and its matrix contains all three components ( Majed et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

GapB Is Involved in Biofilm Formation Dependent on LrgAB but Not the SinI/R System in Bacillus cereus 0-9

Zhang

et al. 2020

Front. Microbiol.

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Bacillus cereus 0-9, a Gram-positive endospore-forming bacterium isolated from healthy wheat roots, has biological control capacity against several soil-borne plant diseases of wheat such as sharp eyespot and take-all. The bacterium can produce various biofilms that differ in their architecture and formation mechanisms, possibly for adapting to different environments. The gapB gene, encoding a glyceraldehyde-3-phosphate dehydrogenase (GAPDH), plays a key role in B. cereus 0-9 biofilm formation. We studied the function of GapB and the mechanism of its involvement in regulating B. cereus 0-9 biofilm formation. GapB has GAPDH activities for both NAD+- and NADP+-dependent dehydrogenases and is a key enzyme in gluconeogenesis. Biofilm yield of the ΔgapB strain decreased by 78.5% compared with that of wild-type B. cereus 0-9 in lysogeny broth supplemented with some mineral salts (LBS), and the ΔgapB::gapB mutants were recovered with gapB gene supplementation. Interestingly, supplementing the LBS medium with 0.1–0.5% glycerol restored the biofilm formation capacity of the ΔgapB mutants. Therefore, GapB regulates biofilm formation relative to its function in gluconeogenesis. To illustrate how GapB is involved in regulating biofilm formation through gluconeogenesis, we carried out further research. The results indicate that the GapB regulated the B. cereus 0-9 biofilm formation independently of the exopolysaccharides and regulatory proteins in the typical SinI/R system, likely owing to the release of extracellular DNA in the matrix. Transcriptome analysis showed that the gapB deletion caused changes in the expression levels of only 18 genes, among which, lrgAB was the most significantly increased by 6.17-fold. We confirmed this hypothesis by counting the dead and living cells in the biofilms and found the number of living cells in the biofilm formed by the ΔgapB strain was nearly 7.5 times than that of wild-type B. cereus 0-9. Therefore, we concluded that the GapB is involved in the extracellular DNA release and biofilm formation by regulating the expression or activities of LrgAB. These results provide a new insight into the regulatory mechanism of bacterial biofilm formation and a new foundation for further studying the stress resistance of B. cereus.

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“…Additionally, Saunders et al suggest that pyocyanin plays an important role in the metabolism of P . aeruginosa biofilm due to its participation in charge transfer processes [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Studies have shown that pyocyanin exerts minor toxic events in the range of 5-10 mg/L in lung epithelial cells (L-132) [13]. Additionally, Saunders et al suggest that pyocyanin plays an important role in the metabolism of P. aeruginosa biofilm due to its participation in charge transfer processes [14].…”

Section: Introductionmentioning

confidence: 99%

Changes in toxin production of environmental Pseudomonas aeruginosa isolates exposed to sub-inhibitory concentrations of three common antibiotics

et al. 2021

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Pseudomonas aeruginosa is an environmental pathogen that can cause severe infections in immunocompromised patients. P. aeruginosa infections are typically treated with multiple antibiotics including tobramycin, ciprofloxacin, and meropenem. However, antibiotics do not always entirely clear the bacteria from the infection site, where they may remain virulent. This is because the effective antibiotic concentration and diffusion in vitro may differ from the in vivo environment in patients. Therefore, it is important to understand the effect of non-lethal sub-inhibitory antibiotic concentrations on bacterial phenotype. Here, we investigate if sub-inhibitory antimicrobial concentrations cause alterations in bacterial virulence factor production using pyocyanin as a model toxin. We tested this using the aforementioned antibiotics on 10 environmental P. aeruginosa strains. Using on-the-spot electrochemical screening, we were able to directly quantify changes in production of pyocyanin in a measurement time of 17 seconds. Upon selecting 3 representative strains to further test the effects of sub-minimum inhibitory concentration (MICs), we found that pyocyanin production changed significantly when the bacteria were exposed to 10-fold MIC of the 3 antibiotics tested, and this was strain specific. A series of biologically relevant measured pyocyanin concentrations were also used to assess the effects of increased virulence on a culture of epithelial cells. We found a decreased viability of the epithelial cells when incubated with biologically relevant pyocyanin concentrations. This suggests that the antibiotic-induced virulence also is a value worth being enclosed in regular testing of pathogens.

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Extracellular DNA Promotes Efficient Extracellular Electron Transfer by Pyocyanin in Pseudomonas aeruginosa Biofilms

Abstract: Highlights d PYO and PCN bind extracellular DNA, which facilitates their retention in biofilms d Electrode biofilms support fast PYO electron transfer and slow PYO loss d Phenazines rapidly exchange electrons and are capable of DNA charge transfer in vitro

Cited by 184 publications

References 81 publications

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

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

GapB Is Involved in Biofilm Formation Dependent on LrgAB but Not the SinI/R System in Bacillus cereus 0-9

Changes in toxin production of environmental Pseudomonas aeruginosa isolates exposed to sub-inhibitory concentrations of three common antibiotics

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