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Bacteriology | Minireview
Multitasking functions of bacterial extracellular DNA inbiolms
Dhirendra Kumar Sharma,1,2 Yogendra Singh Rajpurohit1,2
AUTHOR AFFILIATIONS See aliation list on p. 10.
ABSTRACT Bacterial biolms are intricate ecosystems of microbial communities that
adhere to various surfaces and are enveloped by an extracellular matrix composed of
polymeric substances. Within the context of bacterial biolms, extracellular DNA (eDNA)
originates from cell lysis or is actively secreted, where it exerts a signicant inu-
ence on the formation, stability, and resistance of biolms to environmental stressors.
The exploration of eDNA within bacterial biolms holds paramount importance in
research, with far-reaching implications for both human health and the environment. An
enhanced understanding of the functions of eDNA in biolm formation and antibi
otic resistance could inspire the development of strategies to combat biolm-related
infections and improve the management of antibiotic resistance. This comprehensive
review encapsulates the latest discoveries concerning eDNA, encompassing its origins,
functions within bacterial biolms, and signicance in bacterial pathogenesis.
KEYWORDS extracellular DNA (eDNA), biolm, extracellular polymeric substances
(EPSs), quorum sensing (QS), horizontal gene transfer (HGT)
Bacterial biolms are ubiquitous and complex niches of microbial communities that
adhere to a variety of surfaces (water distribution systems, medical implants, natural
ecosystems, and living tissues/organisms) and are encased in a matrix of extracellular
polymeric substances (EPSs) (1–6). EPS is composed of exopolysaccharides, extracellular
DNA (eDNA), proteins, and amyloidogenic proteins (7–10). The EPS matrix is essen
tial for maintaining a hydrated matrix and promoting optimal conditions for biolm
growth. Furthermore, its distinctive attributes, such as its capacity to absorb and trap
both dissolved and particulate matter from its surroundings, enhance interactions with
various surfaces during biolm formation (9, 11, 12).
Biolms play vital roles in microbiology, from pathogenesis to ecology and biore
mediation (6, 13–15). These bacteria shield inhabitants from environmental changes,
repel antibiotics and immune cells, and foster antibiotic-resistant bacteria in nosoco
mial infections (5, 6, 16–18). Biolms act as enzyme-lled digestive systems, provid
ing nutrients to their inhabitants. Additionally, biolms and their products, such as
metabolites and bacterial membrane vesicles (MVs), directly impact the intestinal
environment of the host and indirectly inuence host health (19).
Studies in model organisms such as Pseudomonas aeruginosa and Burkholderia
cenocepacia suggest cyclic events for biolm formation. This process involves several
steps: (i) adsorption of molecules onto surfaces in reversible and irreversible manners, (ii)
bacterial adhesion accompanied by EPS release, (iii) biolm formation leading to growth,
(iv) maturation, and (v) dispersion or release of planktonic or nonattached aggregates
from biolms (11, 20). The biolm-embedded bacterial communities exhibit altered
metabolic activity, with increased EPS production, gene activation or inhibition related
to biolm formation, and decreased growth (11, 21–26). In contrast to the perspective
that biolm formation arises primarily from individual planktonic cells, it is proposed that
the formation of P. aeruginosa and other bacterial biolms is predominantly driven by
preexisting bacterial nonattached aggregates, as these aggregates may have a better
April 2024 Volume 206 Issue 4 10.1128/jb.00006-24 1
Editor George O'Toole, Geisel School of Medicine at
Dartmouth, Hanover, New Hampshire, USA
Address correspondence to Yogendra Singh
Rajpurohit, ysraj@barc.gov.in.
Dhirendra Kumar Sharma and Yogendra Singh
Rajpurohit contributed equally to this article. Author
order was based on seniority.
The authors declare no conict of interest.
See the funding table on p. 10.
Published 6 March 2024
Copyright © 2024 American Society for
Microbiology. All Rights Reserved.
chance of landing on a surface and facilitating nutrient access (27–29). In addition
to surface-attached biolm formation, recent research highlights the prevalence of
bacterial aggregates in chronic infections caused by dierent bacteria (29). In natural and
environmental settings, similar aggregates are well documented: marine gel particles
formed by bacteria attached to phytoplankton exopolymers, bacteria-laden “snows” in
freshwater systems, and multispecies bacterial “ocs” used in wastewater treatment (30).
eDNAs play signicant roles in biolm formation, stability, and resilience against
environmental stresses (31–42). In recent years, there has been growing interest among
researchers in studying eDNA within biolms to gain insights into the mechanisms
underlying biolm formation, maintenance, and persistence (43–45). In P. aeruginosa,
eDNA has been found to acidify (acidic pH) the environment and provide a protective
shield against aminoglycosides and antimicrobial peptides by the upregulation of PhoPQ
and PmrAB two-component regulatory systems (46). In the case of the human pathogens
Listeria monocytogenes, Campylobacter jejuni, and Helicobacter pylori, eDNA plays a crucial
role in biolm formation by facilitating initial bacterial attachment and biolm initiation
(47–50). Similarly, Staphylococcus aureus relies on eDNA for bacterial attachment, acting
as an electrostatic net that tethers all bacteria together in the biolm (51). eDNA also
contributes to the structural integrity of the biolm matrix, serving as a scaold for
bacterial cell attachment. Moreover, eDNA can act as a chemoattractant, facilitating the
recruitment of new cells to the biolm community (52–55). A recent report suggested
that eDNA released from dying cells acts as a chemorepellent in Caulobacter crescentus
biolms, deterring newborn cells from integrating into the established biolm commun
ity and promoting their dispersal to potentially colonize new environments (56).
Thus, eDNA in bacterial biolms represents a signicant research area with implica
tions for human health and environmental biology (57). By gaining a better understand
ing of the role of eDNA in biolm formation, researchers may develop novel strategies
to prevent and treat biolm-related infections, as well as improve our ability to control
the spread of antibiotic resistance. This review summarizes recent ndings on eDNA,
including its origin, size, conformational diversity, interactions with various biolm
constituents, roles, and signicance in bacterial physiology.
THE eDNA SOURCE IN THE BIOFILM
eDNA release within biolms can occur through lysis-dependent or -independent
pathways (Fig. 1). The lysis-dependent release of eDNA can be triggered by program
med bacterial apoptosis or fratricide-induced death, which is inuenced by quorum
sensing (QS) systems or specic stressors (12, 54, 58–62). Additionally, bacteriophage
and antibiotic exposure can stimulate the lysis-dependent release of eDNA by selectively
killing a portion of bacteria (63–65). Bacteriophage infection is also associated with the
development of membrane blebs on intact bacteria (66). Another potential source of
eDNA in biolms is from small, membrane-bound structures such as extracellular MVs
(67–70). Mechanistically, MVs are released by cells within biolms through an explosive
cell lysis mechanism facilitated by the prophage endolysin encoded within the R- and
F-pyocin gene clusters (58).
Conversely, eDNA can also be produced via lysis-independent mechanisms. eDNA in
biolms is actively secreted DNA by the dynamic T4SS (55, 71–74). The secretion of eDNA
has been observed in several bacteria, including Neisseria gonorrhoeae, H. pylori, and
Variovorax paradoxus (62, 71, 73, 75–78). The active secretion of eDNA may serve various
functions, such as defense mechanisms against other microbes or as a means of
communication between cells. Furthermore, the subunits of the type IV pilus (T4P) are
involved in binding with eDNA, thus facilitating biolm formation, suggesting that the
function of T4P may extend beyond its role in DNA uptake for natural competence (79–
84).
Apart from lysis-dependent and -independent sources, eDNA in biolms can originate
from host tissue cells through bacterial cytolytic or proapoptotic toxins or can be
acquired from NETs (85, 86) (for more details, please refer to The Conformational
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Diversity of eDNA within the Biolm Matrix). Thus, the origin of eDNA within biolms is
complex and multisourced and involves release from dead cells, MVs, active secretion by
living cells, and NETosis (Fig. 1) (55, 60). Table S1 lists the various microorganisms that
produce eDNA and their release mechanisms.
AMOUNT AND SIZE OF eDNA IN BIOFILMS
The amount and size of eDNA in a biolm vary and depend on various factors, such
as the composition of the microorganism, the stage of biolm development, and the
environmental conditions. As the biolm matures, the eDNA content steadily increases,
peaking during the stationary phase (87). The size of eDNA fragments can vary widely,
ranging from a few hundred base pairs to several kilobases (87). Typically, secreted DNA
is smaller than genomic DNA released due to cell death (88, 89). For example, in the case
of H. pylori, the amount of eDNA released from both cell lysis mechanisms is estimated to
be greater than 9.0 kbp within the EPS matrix (47).
The quantity of eDNA in biolm can exhibit signicant variability, ranging from a
small fraction to more than half of the total dry weight of the biolm, depending on the
specic bacterial biolm. For instance, Streptococcus pneumoniae releases approximately
0.5% of its total chromosomal DNA into the extracellular medium (88) through mecha
nisms such as fratricide or predatory lysis, activated by competence stimulating peptide
FIG 1 Source of eDNA within biolms. eDNA release in biolms occurs through both lysis-dependent and -independent mechanisms. Lysis-dependent
mechanisms include programmed bacterial apoptosis, fratricide-induced death, exposure to sublethal doses of antibiotics, and the action of bacteriophages.
Lysis-independent mechanisms include the active secretion of DNA by the type IV secretion system (T4SS), the production of membrane vesicles (MVs) lled with
eDNA, and the formation of neutrophil extracellular traps (NETs) by polymorphonuclear leukocytes/neutrophils.
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(90). In the case of Bacillus subtilis, eDNA release is predominantly observed during the
transition from the exponential growth phase to the stationary phase, followed by a
rapid decrease in eDNA concentration (87). Under QS control, P. aeruginosa is capable of
releasing a substantial amount of double-stranded genomic DNA (up to 18 µg mL−1)
during the late logarithmic growth phase once a certain cell density is reached in
liquid culture (53, 91). N. gonorrhoeae can release signicant amounts of DNA into the
medium via an active eDNA release mechanism (T4SS) (71, 73, 89). In general, eDNA can
constitute a substantial portion of the overall biomass of a biolm.
THE CONFORMATIONAL DIVERSITY OF eDNA WITHIN THE BIOFILM MATRIX
eDNA is a fundamental component of the biolm matrix and contributes to the
formation of a stable lamentous network (Fig. 2A) (9, 92). The signicance of eDNA
in biolm organization, maturation, and initial bacterial attachment to surfaces has
been extensively demonstrated in various pathogenic bacteria (93). The eDNA network
within S. aureus biolms is further stabilized by the interaction of positively charged cell
surface-associated cytoplasmic proteins with eDNA in a pH-sensitive manner; at pH 4.5
to 5, these proteins have a net positive charge, facilitating their interaction with the
proposed eDNA network (94). eDNA within the biolm matrix can assume lamentous
branched structures, including Holliday junction (HJ) DNA, cruciform conformations,
Z-DNA, or G-quadruplex structures (42, 95–101). These structures play essential roles
in maintaining the structural stability and elasticity of eDNA, interacting with EPSs,
protecting against nucleases, and enabling viscoelastic relaxation under mechanical
stress (95, 102–104). Within biolms, eDNA is stabilized by the DNABII protein family,
which includes the histone-like protein HU and the integration host factor IHF (42, 95–
98). Experimental evidence on Staphylococcus epidermidis and Haemophilus inuenzae
biolms shows that the antibody-mediated inhibition of DNABII function (through IHF
binding) or complementing DNABII with Escherichia coli RuvA (a high-anity HJ binder)
results in biolm depletion or stabilization, respectively, supporting the role of eDNA in
its HJ form in biolms (95, 98, 105).
The maintenance of the structural stability and conguration of eDNA in biolms
involves a combination of both bacterial and host-specic proteins (8, 42). Notably,
polymorphonuclear leukocytes (PMNs), the guardians of the innate immune system, can
transform chromatin into NETs (86, 106). This transformation, known as NETosis, can be
induced by infectious virulence factors or immune stimulation (88). NETs are released in a
mesh-like pattern, with the goal of capturing and eliminating individual bacteria or
isolating biolms. However, for the NET strategy to succeed, the native B-form of eDNA
must be maintained (42). Recent ndings suggest the presence of Z-DNA conformations
in the eDNA of biolms, and DNABII proteins can convert NET DNA from the B to Z
conformation, rendering NETosis less eective at protecting against immune evasion,
allowing bacteria to evade capture and potentially cause infection (Fig. 2B) (42, 97).
Therefore, understanding the mechanisms of NET formation and the factors that
inuence NET structure is crucial for developing eective strategies to combat biolm
infections. By targeting DNABII proteins or other factors that disrupt NET integrity, the
ability of the immune system to control biolm growth and protect against biolm-
associated infections can be enhanced. Furthermore, the dynamic remodeling of eDNA
within biolms or the dispersion of biolms is facilitated by secretory nucleases, and the
absence of such extracellular nucleases often results in compact, thick, and unstructured
biolms lacking the characteristic uid-lled channels present in mature three-dimen
sional biolm matrices or impaired dispersion of biolms (107–109). Collectively, the
available evidence indicates that eDNA forms the structural framework of bacterial
biolms, and various forms of DNA conformation may coexist within biolms and
facilitate structural stability, interactions, and biolm remodeling.
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INTERACTIONS OF eDNA WITH BIOFILM CONSTITUENTS
The interaction between eDNA and other biolm components, particularly polysacchar
ides, plays a crucial role in biolm formation for various bacterial species. In staphy
lococcal species such as S. aureus and S. epidermidis, the polysaccharide intercellular
adhesin (PIA) is an exopolysaccharide of biolms that contributes to virulence, antibi
otics, and nitric oxide tolerance (110–114). PIA consists of glycan chains composed
of beta-1,6-linked 2-acetamido-2-deoxy-D-glucopyranosyl residues, with approximately
15% of these residues being non-N-acetylated (111). PIA becomes positively charged
due to partial deacetylation, and it directly interacts with eDNA. One study proposed
an electrostatic network model in which the interaction between PIA and eDNA is
indirectly mediated by membrane lipoproteins, supporting the synergistic function of
eDNA and PIA in biolm formation and bacterial aggregation (51, 115, 116). Interestingly,
a recent report suggested that cell‒cell aggregation in S. epidermidis can be induced
by host factors independent of the major adhesins PIA and Embp (117). This discovery
underscores the need for further studies to comprehend the intricate nature of biolm
formation in S. epidermidis and other clinically relevant strains.
In P. aeruginosa biolms, dierent exopolysaccharides, such as alginate, Psl (a neutral
mannose-rich polysaccharide), and Pel (partially deacetylated N-acetylglucosamine and
FIG 2 Dynamic niche of bacterial biolms and NETs. (A) Biolms are complex communities of bacteria embedded in a self-produced extracellular matrix (ECM)
that provides structural support, protection from environmental insults, and a means of communication. EPSs, a major component of the ECM, interact with
eDNA to form a mesh-like structure that enhances biolm stability and resistance to antibiotic treatment. QS signals, which are molecules that bacteria use to
communicate with each other, trigger the release of eDNA from biolm-associated bacteria. Along with other matrix proteins, the biolm matrix protein DNABII
helps to stabilize the conformation of eDNA and facilitates processes such as horizontal gene transfer (HGT). (B) Neutrophils, the predominant white blood cells
in the immune system, employ a powerful weapon against invading microbes: NETs. These intricate mesh-like structures, composed of eDNA and antimicrobial
proteins, serve as sticky nets to capture and eliminate individual bacteria. In the context of biolms, which are densely packed communities of bacteria that
adhere to surfaces, NETs play a crucial role in preventing biolm growth and spread. However, the eectiveness of NETs hinges on the structural integrity of the
DNA backbone. In its native B-form, eDNA is robust and resilient, enabling NETs to eectively capture and immobilize bacteria. However, certain proteins, such as
DNABII, can induce a structural transition from the B-form to the Z-form DNA. This conformational change weakens the NET structure, compromising its ability to
trap and eliminate bacteria.
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N-acetylgalactosamine), contribute to the biolm matrix (118, 119). Pel exopolysacchar
ide interacts with eDNA, forming molecular cross-links in the stalks of biolm microcol
onies. The interaction between Psl and eDNA oers structural support to the biolm,
inuencing its density and compactness (118). Interestingly, prior research has demon
strated that P. aeruginosa nonattached aggregates are sustained by both Psl and eDNA
(53, 120, 121). Nevertheless, recent ndings have indicated that the nature of aggre
gation support involving Psl and eDNA is dependent on the growth phase. Speci-
cally, during the exponential growth phase, cell aggregation is primarily supported by
cell-associated Psl, as opposed to either eDNA or secreted Psl. In contrast, during the
stationary phase, aggregates are sustained by both Psl and eDNA (122). P. aeruginosa
mutants lacking Pel and/or Psl did not exhibit changes in wound severity when tested
in a mouse wound model. However, parameters such as the bacterial load, wound
closure rate, size, and spatial distribution of biolm aggregates within the wound tissue
were signicantly altered. Additionally, the ability of these mutants to survive antibi
otic treatment was impaired. These ndings suggest that eDNA-associated Pel and Psl
exopolysaccharides may not directly impact P. aeruginosa virulence and likely contribute
to bacterial persistence in vivo (123). For Bacillus subtilis, the main exopolysaccharide
SBE1 might be associated with the expression of the epsG gene, and eDNA was found
to colocalize with SBE1 in B. subtilis pellicles, suggesting a potential physical interaction
between the two (124).
Biolm proteins also play a crucial role in bacterial aggregation and biolm stabiliza
tion (115, 125, 126). Various categories of proteins, including secreted proteins (e.g.,
exotoxin β-toxin), surface proteins (e.g., S. aureus SaeP), and lipoproteins (e.g., S. aureus
IsaB), have been shown to exhibit eDNA-binding, anchoring, and biolm compacting
eects when bound to eDNA in bacterial biolms (115, 127, 128). Additionally, amyloido
genic proteins, including CsgA from E. coli and phenol-soluble modulins from S. aureus,
can form amyloid brils that bind to eDNA, contributing to the increased structural
stability of biolms (99–101, 129). In addition, DNABII family proteins (such as IHF, HU,
and DNABII) attach to the intersections of intertwined eDNA strands and act as pivotal
molecules that enhance the lattice-like structural stability of the eDNA structure within
the biolm (41, 95, 105, 130–132). Furthermore, certain bacterial factors, such as the
lysozyme LytC (extracellular protein) protein of S. pneumoniae and Enterococcus faecalis
PrgB, have been shown to interact with eDNA and may also play a role in stabilizing
biolm architecture (41, 133, 134). Together, both direct and indirect interactions of
eDNA with various biolm polysaccharides and proteins are necessary for its structural
and functional properties, as well as for the maintenance of the biolm.
eDNA AND QUORUM SENSING
QS is a process by which bacteria communicate with each other and coordinate their
behavior based on population density (135–137). QS is mediated by signaling mole
cules, such as acyl-homoserine lactones (AHLs), which are produced and detected by
fellow biolm bacteria (138–140). eDNA can act as a sink for these signaling molecules,
reducing their concentration and interfering with quorum sensing. Recent studies have
shown that AHL-dependent QS impacts the biolm dierentiation, composition, and
antibiotic tolerance of Acinetobacter baumannii (141). It has been shown that eDNA
release within biolm could be controlled by QS-dependent and QS-independent
mechanisms (55). For example, P. aeruginosa eDNA release depends on QS signaling
molecules and QS-independent systems such as agella and type IV pili (53). Addition
ally, there are specic adaptive processes that connect PrrF small RNAs, QS, biolm cell
death, eDNA release, and the heightened biolm formation provoked by tobramycin
in P. aeruginosa (142). Overall, the interactions between eDNA and quorum sensing are
complex phenomena and can vary depending on the specic bacterial species and
environmental conditions involved.
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ROLES OF eDNA IN BIOFILMS
eDNA is a widespread biopolymer found in both terrestrial and aquatic ecosystems
(9, 41, 93). Over the past decade, the importance of eDNA in determining bacterial
physiology and the life cycle of microbial pathogens has gained increased attention, as
it plays essential roles in pathogenicity, transition tness, environmental survival, and
evolution. The following section discusses some of the crucial roles of eDNA in biolms.
eDNAs function as structural stabilizer of biolm
eDNAs play various crucial roles as structural components within biolms (Fig. 2A).
eDNAs stabilize the entire biolm structure. Studies have demonstrated that eDNA in
biolms can adopt various branched structures, such as HJ DNA or cruciform conforma
tions, and these structures stabilize the biolm scaold (refer to The Conformational
Diversity of eDNA within the Biolm Matrix for more detail) (42, 95–101). In P. aerugi
nosa biolms, eDNA accumulates in the stalk region, contributing to structure and cap
formation and directing cell movement toward the cap, with the highest concentration
occurring at the stalk-cap interface, creating a distinct separation between the two
bacterial communities (53, 143). Recent studies have suggested that biolms act as
viscoelastic materials and possess elastic, solid-like, and viscous uid-like properties
(144). The dynamic switch between solidity and uidity allows biolms to resist external
forces, including the relentless onset of phagocytic immune cells (144).
eDNAs orchestrate the viscoelastic properties of biolms by the following mecha
nisms. First, eDNA, along with biolm exopolysaccharides (for example, P. aeruginosa
Psl exopolysaccharide), acts as a molecular glue, weaving through the biolm and
physically tethering bacterial cells together (118). This interconnected network enhances
biolm stiness and resistance to mechanical forces, similar to the tensile strength of a
spiderweb, and eectively thwarts phagocytic immune cells. Interestingly, the viscoe
lastic properties of biolms may also be supported by the incorporation of material
from the environment, such as P. aeruginosa biolms and collagen brils from the host
environment, which enhance the viscoelasticity of biolms (145). Second, eDNA plays a
structural role in the formation of biolm streamers. These long, suspended laments,
formed by the interaction of eDNA with Pel exopolysaccharides of P. aeruginosa, provide
both uidity and mechanical strength in the presence of ow and geometric constraints
(146). Therefore, the viscoelasticity of biolms is not random but rather a carefully
choreographed phenomenon orchestrated by eDNA and exopolysaccharides. Under
standing this intricate change holds immense promise for advancements in various
elds. In healthcare, it can lead to new strategies to combat biolm-associated infec
tions. In industry, it could pave the way for bioinspired materials with superior mechan
ical properties. In environmental management, it can oer insights into controlling
biofouling and biodegradation processes. Thus, revealing the roles of eDNA in determin
ing biolm viscoelasticity and structural stability unlocks a new era of possibilities in
healthcare, industry, and environmental management.
eDNA functions in the adhesion of bacteria during biolm formation
Bacterial adhesion in the initial stage of biolm formation involves a two-step process. In
the rst step, bacterial cells act like colloidal particles, making contact with the surface
based on their physicochemical properties. These interactions are inuenced primarily
by reversible interactions, such as Van der Waals forces, which include attractive and
repulsive forces due to the electrostatic repulsion caused by the negative charge of the
cell membrane and the surface. The second phase involves specic interactions, often
mediated by ligand‒receptor molecules or biological polymers, leading to increased
binding strength over time (147–151). Both of these phases are directly impacted by
eDNA present on the cell surface, with interactions occurring within a range of approx
imately 10 nm (152, 153). eDNAs play a crucial role in short-range interactions, particu
larly by interacting with cations such as Ca2+, thereby mediating bacterial aggregation
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and biolm formation in the second phase (154). This hypothesis has been supported by
research conducted by Das et al. (155), who demonstrated that eDNA forms elonga
ted loop structures up to 300 nm in length, absorbing the surface negative charge
and contributing to bacterial adhesion (155, 156). eDNA also has an impact on the
hydrophobicity and pH of the bacterial cell surface due to the amphiphilic properties
of eDNA (157). It is shown that increasing pH signicantly boosted biolm formation
in all analyzed microorganisms, with the highest levels observed at pH 7.5 and 8.5.
Outside this optimal range, both acidic and alkaline conditions signicantly reduced
adhesion and biolm formation (158–160). In summary, eDNA signicantly inuences the
short-range interactions, alteration of hydrophobicity, and pH of bacterial cell surface
and contributes to the attachment of bacterial cells to surfaces.
eDNA functions as a source of nutrients, HGT, and DNA damage repair
eDNA is prevalent in natural environments and holds potential as a source of energy and
essential nutrients such as carbon, nitrogen, and phosphorus (161–164). Low-phosphate
conditions induce two Vibrio cholerae nucleases, Xds and Dns, leading to the extracellular
accumulation of nucleotides (165). These nucleotides can enter the cell through the
OmpK protein in the outer membrane and are subsequently dephosphorylated by three
periplasmic phosphatases (166). Three NupC nucleoside transport systems enable the
uptake of free nucleosides for carbon and nitrogen utilization (162). The Pst/PhoU system
facilitates phosphate uptake, and V. cholerae can store carbon and phosphate in the
form of glycogen and polyphosphate, respectively (167). The presence of nucleoside
uptake genes contributes to pathogen tness during the transition from a host to
nutrient-depleted environments. The NupC transport system, which is also present in E.
coli, has been identied as a nucleoside transporter in organisms such as S. aureus, H.
pylori, and B. subtilis. In these organisms, nucleosides can serve as an energy source or be
utilized for the de novo synthesis of nucleotides (93, 168–170).
eDNA plays a crucial role in HGT among bacteria, facilitating genetic recombina
tion and promoting evolutionarily favorable traits (Fig. 2A). The transfer of antibiotic
resistance genes through HGT occurs more frequently in biolms than in planktonic
cultures, and various regulatory systems governing competence, biolm formation, QS,
and carbon catabolite repression (CCR) are often linked with eDNA uptake by bacteria
(171–174). Additionally, MVs containing eDNA have been demonstrated to enhance
DNA uptake and genetic recombination eciency (66, 174–179). P. aeruginosa eDNA
can also inuence bacterial gene expression and behavior through other mechanisms,
such as by binding to and regulating the activity of transcription factors or serving
as a nutrient source (180). In the case of C. jejuni, eDNA plays a role in transferring
genetic traits among bacteria within biolms, which may lead to the proliferation of
antimicrobial resistance (181, 182). Vibrio cholerae has been extensively studied for its
ability to regulate competence (183). It induces natural competence when growing on
chitin, a carbon source. The type VI secretion system in V. cholerae promotes predation
on neighboring cells, liberating their DNA, which can act as an eDNA for HGT or a
nutrient source (184–186). The chitin utilization and competence genes in V. cholerae
are positively regulated by the QS regulator HapR, the cytidine repressor CytR, and CRP,
a global regulator of CCR (187, 188). The complex pathway of eDNA degradation in V.
cholerae involves extracellular nucleases, leading to the accumulation of nucleosides. V.
cholerae uses three Na+-dependent nucleoside transport systems to uptake nucleosides
as carbon and nitrogen sources (162). In Streptococcus mutans, QS signals stimulate
eDNA uptake and enhance competence induction (189–192), while in H. inuenzae,
competence is regulated by nucleic acid precursor availability under CRP-dependent
control (193, 194).
The potential roles of eDNA in DNA damage repair were theorized, and it has been
observed that in B. subtilis, the SOS pathway, a comprehensive response to DNA damage,
can be triggered by both DNA-damaging agents and the development of competence
(195). Although the uptake of DNA in B. subtilis is not directly regulated by DNA damage
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(196, 197), the SOS system works in conjunction with eDNA uptake to recognize similar
regions within the genome and engage in recombination to capitalize on any potential
benets (198–200). The master regulator of competence in B. subtilis, ComK, initiates the
transition to a competent state (K-state), governing the expression of various clusters,
some tied to eDNA uptake and others to repair and recombination (recA, dinB) (201–203).
During the K-state, the recombination and replication machinery is closely linked with
the DNA uptake system (204, 205), supplying dierent proteins depending on the type
of DNA assimilated. In contrast, some bacteria lack a conventional SOS response, but
eDNA uptake is benecial for mending genetic mutations. In these cases, competence
is triggered after DNA damage (195, 196, 206, 207). For instance, in S. pneumoniae,
an SOS-like mechanism has not been identied, leading competence to assume the
role of this repair pathway. Exposure to mitomycin C, which damages DNA, prompts
the competence regulatory cascade, which includes the activation of the recA gene,
enabling DNA repair or the acquisition of suppressor mutations that preserve population
tness (208). Thus, in bacteria, the role of eDNA in adaptive evolution, DNA repair, and
nutritional support was shown to be benecial, neutral, and/or contingent upon specic
circumstances. Notably, eDNA uptake may also function as a generalized stress response
(45, 195, 196, 207, 209, 210). Overall, eDNA serves as a pool for nutrients and HGT and
DNA repair within bacterial populations, contributing to the spread of genetic traits and
biolm formation.
Roles of eDNA in pathogenesis
eDNA contributes to biolm resistance against certain antimicrobial agents. P. aerugi
nosa biolm aggregation results in both tolerance and resistance to the host immune
system and antibiotics (Fig. 2A) (211–215). Chronic bacterial infections are particu
larly problematic due to persistent inammation caused by PMNs that surround the
biolm but cannot penetrate and eradicate it. During chronic infections, PMNs undergo
necrosis, releasing toxic compounds such as oxidants, neutrophil elastase, and eDNA,
which contributes to inammation (216–220). Additionally, rhamnolipids released by P.
aeruginosa cause PMN swelling and lysis, releasing nuclear and cytoplasmic contents
that form a biological matrix for biolm formation and contribute to increased toler
ance to tobramycin (221–223). Furthermore, chelating and acidifying abilities bolster
antibiotic resistance, while enhanced cation chelation promotes resistance against
antimicrobial peptides by activating the PhoPQ and PmrAB signaling systems associated
with antimicrobial resistance (46, 224, 225). It has also been shown that when exogenous
DNA is introduced into P. aeruginosa biolms, it is incorporated into the matrix, where it
enhances tolerance to tobramycin by threefold and gentamicin by twofold (211, 226).
Recently, recognizing the contribution of NETs to antibiotic resistance in COVID-19
patients with bacterial coinfections, the use of DNase enzymes to break down these
NETs is gaining traction as a potential therapeutic approach (227). Additionally, eDNA
implications in HGT may confer specic antibiotic (methicillin/vancomycin) resistance
and contribute to bacterial pathogenesis (171, 228–232).
Collectively, eDNA signicantly inuences biolm resistance and provides bacteria
with a mechanism to endure antimicrobial treatments, making it a critical factor in the
pathogenesis of infections. Bacterial biolms play a pivotal role in the onset of var
ious persistent diseases, and the increase in antibiotic-resistant bacteria has signi-
cantly complicated their eective treatment. Consequently, directing attention toward
targeting eDNA within bacterial biolms represents an appealing avenue to counteract
bacterial persistence against antibiotics (45, 98).
CONCLUDING REMARKS
The information summarized in this review shows that eDNA production is a widespread
process, whereas the release mechanisms and functions of eDNA vary considerably
depending on the species. Multiple functions of eDNA have been described, which
makes it an even more interesting molecule. eDNA can not only be used as a nutrient
Minireview Journal of Bacteriology
April 2024 Volume 206 Issue 4 10.1128/jb.00006-24 9
but also interact with other proteins, as demonstrated for many bacteria, such as P.
aeruginosa, S. pneumoniae, and Staphylococcus intermedius, and function as a structural
molecule for biolm stability. Moreover, eDNA can be considered a signaling molecule
that has macromolecular language when associated with other components of biolms.
Taken together, these ndings shed light on a very important process occurring within
microbial communities, where eDNA becomes a polyvalent molecule used for commu
nication, feeding, and genetic exchange and as a viscoelastic structural component in
biolm formation.
AUTHOR AFFILIATIONS
1Molecular Biology Division, Bhabha Atomic Research Centre, Mumbai, India
2Schools of Life Sciences, Homi Bhabha National Institute (DAE—Deemed University),
Mumbai, India
AUTHOR ORCIDs
Yogendra Singh Rajpurohit http://orcid.org/0000-0002-1140-1251
FUNDING
Funder Grant(s) Author(s)
DAE | Bhabha Atomic Research Centre (BARC) RBA4031 Dhirendra Kumar Sharma
Yogendra Singh Rajpurohit
AUTHOR CONTRIBUTIONS
Dhirendra Kumar Sharma, Resources, Writing – original draft | Yogendra Singh Rajpurohit,
Conceptualization, Data curation, Visualization, Writing – original draft, Writing – review
and editing
ADDITIONAL FILES
The following material is available online.
Supplemental Material
Table S1 (JB00006-24-S0001.docx). Various microorganisms that produce eDNA and
their release mechanisms.
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14
AUTHOR BIOS
Dhirendra Kumar Sharma has been
employed as a Scientic Ocer D in
Bhabha Atomic Research Centre (BARC),
Mumbai (India). He earned a Bachelor
of Science (BSc.) in Biotechnology with
honors from Anugrah Narayan College
Patna, a Magadh University aliate.
Later, he advanced his biotechnology
expertise by earning a Master of Science
(MS) in Biotechnology from the University of Hyderabad,
Hyderabad, a course funded by India's Department of Biotech
nology (DBT). As a Scientic Ocer C, he began research on a
radioresistance bacterium, Deinococcus radiodurans R1, in 2017.
Later, in 2017, he started his Ph.D. in life science at Homi Bhabha
National Institute, Mumbai. Mr. Sharma’s research interests are
in the area of DNA repair, bacterial natural transformation, and
bacterial kinases.
Yogendra Singh Rajpurohit (Ph.D.)
began his academic journey at JNV
University in Jodhpur, Rajasthan, where
he earned his B.Sc. in Biology. Driven
by his passion for biotechnology, he
pursued an M.Sc. in the same eld
at HNB Garhwal Central University,
completing it in 2004. In 2005, Dr.
Rajpurohit joined BARC, Mumbai, India,
as a Scientic Ocer C. He then embarked on his doctoral
studies, earning a Ph.D. in Life Sciences from HBNI, Mumbai, in
2012. Currently, he holds the position of Associate Professor at
HBNI, while maintaining his permanent position as a Scientic
Ocer G post at the Molecular Biology Division of Bhabha
Atomic Research Centre. Dr. Rajpurohit's research interests lie in
research areas like DNA repair, bacterial natural transformation,
signal transduction mechanisms involving serine/threonine/tyro
sine protein kinases, and the complexities of the gut microbiome.
Minireview Journal of Bacteriology
April 2024 Volume 206 Issue 4 10.1128/jb.00006-2417
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