Extracellular DNA Chelates Cations and Induces Antibiotic Resistance in Pseudomonas aeruginosa Biofilms

By H. Mulcahy, Laetitia Charron-Mazenod, S. Lewenza. PLoS Pathogens, 2008

690 citations recorded by the source corpus.

Biofilms are surface-adhered bacterial communities encased in an extracellular matrix composed of DNA, bacterial polysaccharides and proteins, which are up to 1000-fold more antibiotic resistant than planktonic cultures. To date, extracellular DNA has been shown to function as a structural support to maintain Pseudomonas aeruginosa biofilm architecture. Here we show that DNA is a multifaceted component of P. aeruginosa biofilms. At physiologically relevant concentrations, extracellular DNA has antimicrobial activity, causing cell lysis by chelating cations that stabilize lipopolysaccharide (LPS) and the outer membrane (OM). DNA-mediated killing occurred within minutes, as a result of perturbation of both the outer and inner membrane (IM) and the release of cytoplasmic contents, including genomic DNA. Sub-inhibitory concentrations of DNA created a cation-limited environment that resulted in induction of the PhoPQ- and PmrAB-regulated cationic antimicrobial peptide resistance operon PA3552–PA3559 in P. aeruginosa. Furthermore, DNA-induced expression of this operon resulted in up to 2560-fold increased resistance to cationic antimicrobial peptides and 640-fold increased resistance to aminoglycosides, but had no effect on β-lactam and fluoroquinolone resistance. Thus, the presence of extracellular DNA in the biofilm matrix contributes to cation gradients, genomic DNA release and inducible antibiotic resistance. DNA-rich environments, including biofilms and other infection sites like the CF lung, are likely the in vivo environments where extracellular pathogens such as P. aeruginosa encounter cation limitation.

Subfields: Microbiology, Molecular Biology, Molecular Medicine

View Paper: https://www.semanticscholar.org/paper/392be2a83cb338109d3006d5b680f9d583a70204

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Citations in the corpus

Role of the Biofilms in Wastewater Treatment (2016, background): “Recent studies showed that eDNA chelates divalent cations that help in the modification of bacteri‐ al cell surface properties and thus favor resistance of biofilms to detergents and antimicrobi‐ al agents [33].”
Pseudomonas aeruginosa Lifestyle: A Paradigm for Adaptation, Survival, and Persistence (2017, background): “However, eDNA has multifaceted roles in biofilm formation such as contribution to forming cation gradients in the matrix via the chelating interaction of highly anionic DNAwith cations such asMg2+, Ca2+, Mn2+, and Zn2+, as a nutrient source during starvation, facilitating twitching motility and coor”
Oral multispecies biofilm development and the key role of cell–cell distance (2010, background): “Extracellular DNA is an important component of monospecies and multispecies biofilms that are formed by many Gram-positive and Gram-negative bacteri”
The role of bacterial biofilms in chronic infections (2013, background): “, the presence of several layers of bacteria promotes the development of nutrient and oxygen gradients (34) and slows down growth in the core of the aggregate; and (ii) the matrix components can bind and/or neutralize antimicrobial agents (104).”
Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview (2017, background): “DNA acts as a chelating agent for cations due to its phosphodiester skeleton, rendering it capable of disrupting the external and internal membranes of Pseudomonas aeruginosa (10, 11).”
Microbial biofilm: formation, architecture, antibiotic resistance, and control strategies (2021, background): “[125] demonstrated the induction of eDNA-mediated antibiotic resistance in P.”
NETosis: how vital is it? (2013, background): “NET chelation of cations may also contribute to the killing of the opportunistic pathogen P aeruginosa.(82) Whereas NETs are sufficient to kill Pseudomonas grown in suspension, during diseases such as cystic fibrosis, the bacteria changes to a mucoid type and can become NET resistant.”
Assembly and Development of the Pseudomonas aeruginosa Biofilm Matrix (2009, background): “Dead cells, which have a compromised cell membrane, eventually release DNA that could be incorporated into the eDNA matrix or accelerate cell death and lysis [20].”
Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies. (2013, background): “This, in turn, leads to aminoarabinosylation of the lipid A and makes the cells adaptively resistant to cationic peptides and aminoglycosides [37].”
Biofilms as Promoters of Bacterial Antibiotic Resistance and Tolerance (2020, background): “Studies in Pseudomonas evidence that eDNA enhances resistance of biofilms to aminoglycosides but not to fluoroquinolones or β-lactams [73,74].”