Extracellular DNA-induced antimicrobial peptide resistance mechanisms in Pseudomonas aeruginosa

Abstract

Extracellular DNA (eDNA) is in the environment, bodily fluids, in the matrix of biofilms, and accumulates at infection sites. eDNA can function as a nutrient source, a universal biofilm matrix component, and an innate immune effector in eDNA traps. In biofilms, eDNA is required for attachment, aggregation, and stabilization of microcolonies. We have recently shown that eDNA can sequester divalent metal cations, which has interesting implications on antibiotic resistance. eDNA binds metal cations and thus activates the Mg2+-responsive PhoPQ and PmrAB two-component systems. In Pseudomonas aeruginosa and many other Gram-negative bacteria, the PhoPQ/PmrAB systems control various genes required for virulence and resisting killing by antimicrobial peptides (APs), including the pmr genes (PA3552–PA3559) that are responsible for the addition of aminoarabinose to lipid A. The PA4773–PA4775 genes are a second DNA-induced cluster and are required for the production of spermidine on the outer surface, which protects the outer membrane from AP treatment. Both modifications mask the negative surface charges and limit membrane damage by APs. DNA-enriched biofilms or planktonic cultures have increased antibiotic resistance phenotypes to APs and aminoglycosides. These dual antibiotic resistance and immune evasion strategies may be expressed in DNA-rich environments and contribute to long-term survival.

Chelation of Membrane-Bound Cations by Extracellular DNA Activates the Type VI Secretion System in Pseudomonas aeruginosa

“…Extracellular DNA (eDNA) is present in many different environments, including soil, water, sediment, and gastrointestinal and respiratory tracts (41)(42)(43)(44). The physiological functions of eDNA include horizontal gene transfer, nutrient source, and bio-film formation (43,45,46).…”

Surface Polysaccharide Mutants Reveal that Absence of O Antigen Reduces Biofilm Formation of Actinobacillus pleuropneumoniae

“…Treatment with dispersin B completely dispersed preformed biofilms, thereby confirming that PGA is a key scaffolding component of the matrix (4,26). Within the biofilms of P. aeruginosa and Staphylococcus aureus, eDNA is required for the attachment, aggregation, and stabilization of microcolonies, and DNase treatment removes the biofilms (55,56). While we detected eDNA within the biofilm matrix of our parental and mutant A. pleuropneumoniae strains, DNase I treatment did not disperse the preformed biofilms.…”

Current Research Approaches to Target Biofilm Infections.

“…They are also very hydrophobic, which enhances their antimicrobial activity as they are able to interact with bacterial membranes (22). Most AMPs have direct antimicrobial activity by disrupting bacterial membranes, and others have immune modulating activity without strong direct antimicrobial effects (8). A variety of natural and synthetic peptides have recently been shown to have a novel antibiofilm activity against both Gram-positive and Gram-negative bacteria (23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”

“…Biofilms have been demonstrated to be more than 1000fold resistant to treatment with conventional antibiotics normally used to treat planktonic cells (6). Resistance to antibiotics in biofilms is multifactorial and due to poor penetration of antibiotics into the biofilm through the ECM, the presence of multidrug resistant persister cells, slow growth rates and antibiotic indifference, as well as the expression of specific resistance mechanisms of cells within biofilms (6)(7)(8).…”