Hubbry Logo
Plasmid-mediated resistancePlasmid-mediated resistanceMain
Open search
Plasmid-mediated resistance
Community hub
Plasmid-mediated resistance
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Plasmid-mediated resistance
Plasmid-mediated resistance
Plasmid-mediated resistance
View on Wikipedia
from Wikipedia

An example plasmid with two areas of antibiotic resistance coding DNA (1,2) and an origin of replication (3).

Plasmid-mediated resistance is the transfer of antibiotic resistance genes which are carried on plasmids.[1] Plasmids possess mechanisms that ensure their independent replication as well as those that regulate their replication number and guarantee stable inheritance during cell division. By the conjugation process, they can stimulate lateral transfer between bacteria from various genera and kingdoms.[2] Numerous plasmids contain addiction-inducing systems that are typically based on toxin-antitoxin factors and capable of killing daughter cells that don't inherit the plasmid during cell division.[3] Plasmids often carry multiple antibiotic resistance genes, contributing to the spread of multidrug-resistance (MDR).[4] Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by Gram-negative bacteria, especially family Enterobacteriaceae.[5] The global spread of MDR plasmids has been enhanced by selective pressure from antimicrobial medications used in medical facilities and when raising animals for food.[6]

Properties of resistance plasmids

[edit]

Resistance plasmids by definition carry one or more antibiotic resistance genes.[7] They are frequently accompanied by the genes encoding virulence determinants,[8] specific enzymes or resistance to toxic heavy metals.[9] Multiple resistance genes are commonly arranged in the resistance cassettes.[7] The antibiotic resistance genes found on the plasmids confer resistance to most of the antibiotic classes used nowadays, for example, beta-lactams, fluoroquinolones and aminoglycosides.[10]

It is very common for the resistance genes or entire resistance cassettes to be re-arranged on the same plasmid or be moved to a different plasmid or chromosome by means of recombination systems. Examples of such systems include integrons, transposons, and ISCR-promoted gene mobilization.[7]

Most of the resistance plasmids are conjugative, meaning that they encode all the needed components for the transfer of the plasmid to another bacterium,[11] and that isn't present in mobilizable plasmids. According to that, Mobilizable plasmids are smaller in size (usually < 10 kb) while conjugative plasmids are larger (usually > 30 kb) due to the considerable size of DNA required to encode the conjugation mechanisms that allow for cell-to-cell conjugation.[7]

R-factor

[edit]
This section is about the plasmid. For information about the residual factor in crystallography, see R-factor (crystallography).

R-factors are also called resistance factors or resistance plasmids. They are tiny, circular DNA elements that are self-replicating and contain antibiotic resistance genes.[citation needed] They were first found in Japan in 1959 when it was discovered that some Shigella strains had developed resistance to a number of antibiotics used to treat a dysentery epidemic. Shigella is a genus of Gram-negative, aerobic, non-spore-forming, non-motile, rod-shaped bacteria.[citation needed] Resistance genes are ones that give rise to proteins that modify the antibiotic or pump it out. They are different from mutations that give bacteria resistance to antibiotics by preventing the antibiotic from getting in or changing the shape of the target protein.[12] R-factors have been known to contain up to ten resistance genes. They can also spread easily as they contain genes for constructing pili, which allow them to transfer the R-factor to other bacteria.[13] R-factors have contributed to the growing antibiotic resistance crisis because they quickly spread resistance genes among bacteria.[14] The R factor by itself cannot be transmitted.[citation needed]

Structure of Resistance Plasmids

[edit]

The majority of the R-RTF (Resistance Transfer Factor) genes are found in the R-factor (resistance plasmid), which can be conceptualized as a circular piece of DNA with a length of 80 to 95 kb.[citation needed] This plasmid shares many genes with the F factor and is largely homologous to it.[15] Additionally, it has a fin 0 gene that inhibits the transfer operon's functionality. The size and number of drug resistance genes in each R factor varies. For example, the RTF is bigger than the R determinant. An IS 1 element separates the RTF and R determinant on either side before they combine into a single unit. The IS 1 components simplify it for R determinants to be transferred between different R-RTF unit types.[citation needed]

Functions of Resistance Plasmids

[edit]
  • They play a role in the autonomous replication, conjugation, and ampicillin resistance genes.[citation needed]
  • Genes in the resistance plasmids enable bacteria to produce pili and develop resistance to antibiotics.[7]
  • MDR genes in bacteria are transmitted mainly through the resistance plasmids.[4]

Transmission

[edit]

Bacteria containing F-factors (said to be "F+") have the capability for horizontal gene transfer; they can construct a sex pilus, which emerges from the donor bacterium and ensnares the recipient bacterium, draws it in,[16] and eventually triggers the formation of a mating bridge, merging the cytoplasms of two bacteria via a controlled pore.[17] This pore allows the transfer of genetic material, such as a plasmid. Conjugation allows two bacteria, not necessarily from the same species, to transfer genetic material one way.[18] Since many F+ bacteria contain R-factors, antibiotic resistance can be easily spread among a population of bacteria.[19] Also, R-factors can be taken up by "DNA pumps" in their membranes via transformation,[20] or less commonly through viral-mediated transduction[21] via bacteriophages; however, conjugation is the most common means of antibiotic resistance spread. They contain the gene called RTF (Resistance transfer factor).

Enterobacteriaceae

[edit]
Escherichia coli bacteria on the right are sensitive to two beta-lactam antibiotics, and do not grow in the semi-circular regions surrounding the antibiotics. E. coli bacteria on the left are resistant to beta-lactam antibiotics, and grow next to one antibiotic (bottom) and are less inhibited by another antibiotic (top).

it is a family of Gram-negative rod-shaped (bacilli) bacteria, the pathogenic bacteria that are most frequently found in the environment and clinical cases, as a result, they are significantly impacted by the use of antibiotics in agriculture, the ecosystem, or the treatment of diseases.[22] In Enterobacteriaceae, 28 different plasmid types can be identified by PCR-based replicon typing (PBRT).The plasmids that have been frequently reported [IncF, IncI, IncA/C, IncL (previously designated IncL/M), IncN, and IncH] contain a broad variety of resistance genes.[23]

Members of family Enterobacteriaceae, for example, Escherichia coli or Klebsiella pneumoniae pose the biggest threat regarding plasmid-mediated resistance in hospital- and community-acquired infections.[5]

Beta-lactam resistance

[edit]

B-lactamases are antibiotic-hydrolyzing enzymes that typically cause resistance to b-lactam antibiotics. These enzymes are prevalent in Streptomyces, and together with related enzymes discovered in pathogenic and non-pathogenic bacteria, they form the protein family known as the "b-lactamase superfamily".[12] it is hypothesized that b-lactamases also serve a double purpose, such as housekeeping and antibiotic resistance.[24]

Both narrow spectrum beta-lactamases (e.g. penicillinases) and extended spectrum beta-lactamases (ESBL) are common for resistance plasmids in Enterobacteriaceae. Often multiple beta-lactamase genes are found on the same plasmid hydrolyzing a wide spectrum of beta-lactam antibiotics.[5]

Extended spectrum beta-lactamases (ESBL)

[edit]

ESBL enzymes can hydrolyze all beta-lactam antibiotics, including cephalosporins, except for the carpabepenems. The first clinically observed ESBL enzymes were mutated versions of the narrow spectrum beta-lactamases, like TEM and SHV. Other ESBL enzymes originate outside of family Enterobacteriaceae, but have been spreading as well.[5]

In addition, since the plasmids that carry ESBL genes also commonly encode resistance determinants for many other antibiotics, ESBL strains are often resistant to many non-beta-lactam antibiotics as well,[25] leaving very few options for the treatment.

Carbapenemases

[edit]

Carbapenemases represent type of ESBL which are able to hydrolyze carbapenem antibiotics that are considered as the last-resort treatment for ESBL-producing bacteria. KPC, NDM-1, VIM and OXA-48 carbapenemases have been increasingly reported worldwide as causes of hospital-acquired infections.[5]

Quinolone resistance

[edit]

Several studies have shown that fluoroquinolone resistance has enhanced worldwide, especially in Enterobacteriaceae members. QnrA was the first known plasmid-mediated gene associated in quinolone resistance.[26] Quinolone resistance genes are frequently located on the same plasmid as the ESBL genes.[27] The proteins known as QnrS, QnrB, QnrC, and QnrD are four others that are similar. Numerous variants have been found for qnrA, qnrS, and qnrB, and they are distinguished by sequential numbers.[28] The qnr genes can be discovered in integrons and transposons on MDR plasmids of various incompatibility groups, which could carry a number of resistance-related molecules, such as carbapenemases and ESBLs.[29] Examples of resistance mechanisms include different Qnr proteins, aminoglycose acetyltransferase aac(6')-Ib-cr that is able to hydrolyze ciprofloxacin and norfloxacin, as well as efflux transporters OqxAB and QepA.[5]

Aminoglycoside resistance

[edit]

xResistance to aminoglycosides in Gram-negative pathogens is primarily caused by enzymes that acetylate, adenylate, or phosphorylate the medication.[30] On mobile elements, such as plasmids, are the genes that encode these enzymes.[31]Aminoglycoside resistance genes are also commonly found together with ESBL genes. Resistance to aminoglycosides is conferred via numerous aminoglycoside-modifying enzymes and 16S rRNA methyltransferases.[5] Resistance to aminoglycosides is conferred via numerous mechanisms:

  1. aminoglycoside-modifying enzymes and inactivation of the aminoglycosides, which is frequently seen in both gram-positive and gram-negative bacteria and is induced by nucleotidyltransferases, phosphotransferases, or aminoglycoside acetyltransferases.
  2. reduced permeability.
  3. enhanced efflux.
  4. variations to the 30S ribosomal subunit that prevent aminoglycosides from binding to it.[32]

small RNAs

[edit]

Study investigating physiological effect of pHK01 plasmid in host E.coli J53 found that the plasmid reduced bacterial motility and conferred resistance to beta-lactams. The pHK01 produced plasmid-encoded small RNAs and mediated expression of host sRNAs. These sRNAs were antisense to genes involved in replication, conjugate transfer and plasmid stabilisation : AS-repA3 (CopA), AS-traI, AS-finO, AS-traG, AS-pc02 . The over-expression of one of the plasmid-encoded antisense sRNAs: AS-traI shortened t lalog phase of host growth.[33]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Plasmid-mediated resistance

View on Grokipedia
from Grokipedia
Plasmid-mediated resistance refers to the acquisition of antibiotic resistance in bacteria through the horizontal transfer of resistance genes encoded on plasmids, which are small, extrachromosomal, self-replicating DNA molecules capable of autonomous replication and mobility between bacterial cells. These plasmids enable bacteria to rapidly disseminate resistance to a wide array of antibiotics, including critical last-resort drugs such as colistin and carbapenems, thereby undermining antimicrobial therapies. The primary mechanism driving plasmid-mediated resistance is (HGT), predominantly via conjugation, where plasmids are directly transferred between donor and recipient , often across different species and genera. Broad-host-range plasmids, such as those belonging to the Inc groups, facilitate this inter-habitat spread, linking resistance reservoirs in human, animal, and environmental settings under the framework. This mobility is enhanced by the modular structure of plasmids, which can acquire multiple resistance genes (e.g., blaKPC for resistance or mcr-1 for resistance) through recombination events, creating multidrug-resistant strains. Approximately half of plasmid-encoded resistance genes are shared across these diverse habitats, underscoring the global scale of dissemination. In clinical contexts, plasmid-mediated resistance significantly contributes to the rise of "superbugs," such as ST131 and ST258/ST11, which cause severe nosocomial infections and are associated with increased mortality rates in hospital settings. Notable examples include the emergence of mcr-1 in animal populations in during the mid-2000s, which rapidly spread to over 30 countries via food chains and travel, and the KPC-encoding plasmids driving carbapenem-resistant outbreaks in healthcare facilities. These dynamics impose substantial burdens, including prolonged hospitalizations and elevated treatment costs, with overall linked to 1.27 million direct deaths globally in 2019. Addressing this challenge requires integrated , reduced in and , and innovative strategies like plasmid-targeted therapies to curb HGT.

Overview and Fundamentals

Definition and Scope

Plasmid-mediated resistance refers to the acquisition and expression of resistance genes (ARGs) carried on elements called plasmids, which are autonomously replicating, circular genetic structures in . These plasmids enable to withstand s or other antimicrobials by encoding mechanisms such as enzymatic degradation or efflux pumps. Unlike chromosomal resistance, which is integrated into the and primarily passed vertically to daughter cells, plasmid-mediated resistance is characterized by its mobility, allowing between unrelated bacterial strains or , often through conjugation—a process involving direct cell-to-cell contact. The scope of plasmid-mediated resistance encompasses primarily bacterial pathogens, with a pronounced prevalence in Gram-negative species such as , , and other , though it also occurs in Gram-positive bacteria like . This mobility distinguishes it from fixed chromosomal resistance, as plasmids can disseminate ARGs rapidly across diverse ecological niches, including clinical, environmental, and agricultural settings. Plasmids frequently harbor clusters of multiple ARGs, facilitating simultaneous resistance to several drug classes and promoting the emergence of multi-drug resistant (MDR) phenotypes that complicate treatment. Biologically, plasmid-mediated resistance drives accelerated evolution of by enabling efficient , which outpaces mutation-based chromosomal changes and allows to adapt swiftly to selective pressures from antibiotics. This process exacerbates the global burden of MDR infections, undermining therapeutic efficacy and contributing to 1.27 million direct deaths from resistant in 2019, according to a 2022 global burden study. Plasmids are implicated in a of transferable resistance cases, particularly through multi-gene cassettes where approximately 78% of resistance plasmids carry multiple ARGs.

Historical Development

The discovery of plasmid-mediated resistance began in the late 1950s, when Japanese researchers observed transferable multi-drug resistance among Shigella strains isolated from dysentery patients. In 1959, Tomoichiro Akiba and colleagues reported the first evidence of this phenomenon, demonstrating that resistance to multiple antibiotics, including chloramphenicol, streptomycin, tetracycline, and sulfonamides, could be transferred between Shigella flexneri and Escherichia coli through a non-chromosomal mechanism, later identified as conjugation. This finding, initially termed "infective heredity," marked the initial recognition of extrachromosomal elements facilitating resistance spread, though the genetic basis remained unclear at the time. Building on earlier groundwork in bacterial genetics, such as Joshua Lederberg and Edward Tatum's 1946 demonstration of genetic recombination via conjugation in E. coli, these observations laid the foundation for understanding horizontal gene transfer in pathogens. By the 1960s, the term "R-factors" (resistance factors) was coined to describe these mobile elements, primarily through the work of Tsutomu Watanabe, who in 1963 provided a comprehensive review linking them to episomes—self-replicating DNA capable of integration into the bacterial chromosome. The 1970s brought molecular confirmation that R-factors were conjugative plasmids, with studies isolating and characterizing their circular DNA structure, revealing tra operons essential for cell-to-cell transfer. This era solidified plasmids as key vectors for resistance dissemination. In the 1980s, further advances identified mobile genetic elements like transposons within plasmids, enabling gene jumping between replicons, and integrons as capture systems for resistance cassettes; the term "integron" was formally introduced in 1989 by Hall and Stokes to describe these recombination platforms. The 2000s witnessed a surge in global surveillance efforts, driven by the emergence of plasmid-borne carbapenemases like NDM-1, first identified in 2008 in from a Swedish patient with travel history to and rapidly spreading worldwide by 2010. The leveraged whole-genome sequencing to uncover vast plasmid diversity, showing how incompatibility groups and modular architectures facilitate resistance gene accumulation and interspecies transfer. This period highlighted the shift from primarily hospital-acquired infections to community dissemination, exacerbated by international travel and agricultural use. By 2025, post-COVID-19 surges in resistance have intensified this crisis, with overuse of broad-spectrum antibiotics during the pandemic doubling rates of plasmid-mediated carbapenem resistance in pathogens like Klebsiella pneumoniae, persisting in both clinical and environmental settings.

Structure and Components

Physical and Genetic Organization

Plasmid-mediated resistance primarily involves extrachromosomal DNA elements that confer antibiotic resistance to bacterial hosts, with their physical architecture enabling efficient replication and segregation. These plasmids are typically circular, double-stranded DNA molecules ranging in size from approximately 5 to 200 kilobases (kb), though some resistance plasmids can be as small as 2 kb or exceed 200 kb in larger conjugative forms. Smaller plasmids, often under 25 kb, tend to maintain high copy numbers (50–100 copies per cell), facilitating rapid dissemination of resistance genes, while larger ones (over 100 kb) exhibit low copy numbers (1–5 copies per cell) to minimize metabolic burden on the host. This inverse relationship between size and copy number is governed by replication control mechanisms, ensuring plasmid stability across generations. Stability is further enhanced by partitioning systems that promote equitable distribution during . Low-copy plasmids commonly employ active partitioning modules, such as the ParABS system (Type I), where ParA and ParB proteins interact with parS DNA sequences near the origin to actively segregate copies to daughter cells, or the sopA/sopB system in F-like plasmids. High-copy plasmids rely more on random segregation due to their abundance, supplemented by toxin-antitoxin (TA) systems, like CcdAB or VapBC, which induce post-segregational killing of plasmid-free cells to favor retention. These mechanisms collectively ensure long-term persistence, even in the absence of selective pressure. Genetically, resistance plasmids are organized into a conserved backbone and variable accessory regions, with the (ori) serving as the central hub. The backbone includes essential rep genes encoding replicases that initiate at iteron-based or RNA-regulated oris, such as ColE1-type for high-copy plasmids or iteron sequences in low-copy ones. Variable regions, often comprising 20–50% of the , harbor clustered resistance loci within mobile elements like integrons and transposons, allowing modular acquisition of . Integrons feature a promoterless cassette array integrated via an integrase (intI), enabling cassette exchange, while transposons (e.g., Tn3 family) provide mobility through insertion sequences flanking resistance determinants. A typical plasmid map illustrates this : the circular backbone encircles the ori and rep genes adjacent to partitioning loci (e.g., par or ), with variable regions inserted as arcs containing arrays or transposon islands for resistance cassettes, distinct from the transfer (tra) module that supports dissemination. This organization promotes genetic mosaicism, where backbone stability supports the flexible incorporation of accessory elements without disrupting core functions.

Classification of Resistance Plasmids

Resistance plasmids are primarily classified based on their transmissibility, which determines their potential for and spread among bacterial populations. Conjugative plasmids are self-transmissible, possessing all necessary genes for conjugation, including those encoding type IV secretion systems for direct cell-to-cell transfer; prominent examples include IncF plasmids, which are common in and facilitate the dissemination of multiple resistance genes. Mobilizable plasmids lack complete conjugation machinery but can be transferred with the aid of helper conjugative plasmids, relying on relaxase and origin of transfer sequences; IncQ plasmids, such as those in , exemplify this type and often carry resistance determinants despite their smaller size. Non-mobilizable plasmids cannot undergo conjugation and are typically more stable within a host but have limited spread, serving as reservoirs for resistance genes that may later integrate into mobilizable elements. Compatibility groups, denoted as incompatibility (Inc) groups, further classify plasmids based on their replication control mechanisms, which prevent stable co-existence of plasmids with identical or similar replication origins within the same bacterial cell due to interference in partitioning during division. Key Inc groups associated with resistance include IncP, known for its broad-host-range capabilities and carriage of genes for heavy metal and resistance, and IncN, which often harbors and resistance genes while allowing limited co-residence with other groups. Other notable groups are IncF, prevalent in Gram-negative pathogens and typically encoding multi-drug resistance, and IncA/C, which supports transfer of extended-spectrum genes. These groups influence plasmid persistence by dictating whether multiple resistance elements can accumulate in a single host, thereby enhancing overall resistance profiles. Functionally, resistance plasmids are categorized by host range and the spectrum of resistance they confer, affecting their and evolutionary success. Broad-host-range plasmids, such as those in IncP and IncN groups, can replicate and transfer across diverse bacterial species, including Alpha-, Beta-, and , promoting widespread dissemination of resistance beyond specific pathogens. In contrast, narrow-host-range plasmids, like many IncF variants, are restricted primarily to , limiting their inter-species transfer but enabling rapid evolution within high-density populations such as the gut . Multi-drug resistance plasmids, which carry multiple resistance genes (e.g., for beta-lactams, aminoglycosides, and tetracyclines), predominate in clinical isolates and amplify selective pressures, whereas single-drug plasmids provide targeted resistance but are less versatile in evolving antibiotic environments. Specific examples illustrate these classifications' implications for resistance dynamics. IncHI plasmids, particularly IncHI2, are conjugative and prevalent in , often mediating resistance to multiple antibiotics including and sulfonamides, contributing to outbreaks in foodborne pathogens. Updated classifications from plasmid multilocus sequence typing (MLST) databases, such as PubMLST's schemes for IncF, IncN, and IncHI groups, and the PLSDB 2025 update, refine these categories by integrating genomic sequences to track replicon diversity and host associations, revealing ongoing evolution in resistance backbones as of late 2024. These systems highlight how Inc group typing, combined with relaxase-based mobility predictions, aids in surveillance of -mediated resistance spread.

Mechanisms of Resistance

Enzymatic and Efflux-Based Resistance

Plasmid-mediated enzymatic resistance primarily involves the production of enzymes that chemically modify or degrade antibiotics, rendering them inactive. Beta-lactamases, encoded by genes such as bla, hydrolyze the β-lactam ring in penicillins and cephalosporins, preventing their interaction with penicillin-binding proteins in the bacterial cell wall. These enzymes, often classified as class A serine β-lactamases like TEM and SHV variants, arise from point mutations in chromosomal genes that are subsequently mobilized to plasmids via transposons such as Tn1 or Tn3. For instance, TEM-3 derives from TEM-1 through substitutions like Gly238Ser, conferring resistance to oxyimino-cephalosporins. Similarly, CTX-M enzymes, originating from Kluyvera species and carried on IncF plasmids, preferentially hydrolyze cefotaxime. Aminoglycoside-modifying enzymes (AMEs), encoded by genes like aac for acetyltransferases and aph for phosphotransferases, inactivate aminoglycosides by adding acetyl, phosphate, or adenyl groups to hydroxyl or amino moieties on the antibiotic's sugar rings, blocking ribosomal binding. Acetyltransferases such as AAC(3)-II and AAC(6′)-Ib, often found on plasmids like pJHCMW1, modify drugs like and gentamicin. Phosphotransferases like APH(3′)-IIIa, encoded on plasmids in , target kanamycin and neomycin. These enzymes are bifunctional in some cases, such as AAC(6′)-Ie-APH(2″)-Ia, enhancing broad-spectrum resistance. Efflux-based resistance relies on plasmid-encoded pumps that actively export antibiotics from the bacterial or , reducing intracellular concentrations below lethal levels. These pumps, powered by the proton motive force, function as secondary transporters or antiporters. In , the QacA pump, an small multidrug resistance (SMR) family member encoded on plasmids, expels quaternary ammonium compounds and antiseptics like . In , plasmid-borne resistance-nodulation-division (RND) pumps like OqxAB, found on IncHI2 plasmids in and species, export multiple drugs including fluoroquinolones and via a tripartite complex involving an outer factor like TolC. The genetic basis for these mechanisms often involves integrons, mobile elements on plasmids that capture and express resistance cassettes. Class 1 integrons, prevalent in 22–55% of Gram-negative clinical isolates, contain an integrase (intI) and promoter (Pc) that arrange gene cassettes like bla_{OXA} for β-lactamases or aac and qac for modifying enzymes and efflux pumps. These cassettes, flanked by 59-be elements, are inserted at the attI site, enabling recombination and dissemination via conjugative plasmids. For example, Tn402-like transposons link integrons to bla and aac genes, promoting their transfer. Efficiency of these mechanisms depends on and pump specificity. For β-lactamases, catalytic efficiency (k_{cat}/K_m) measures rate; plasmid-mediated AmpC enzymes like CMY-2 exhibit a low K_m of 0.0012 μM for , indicating high substrate affinity compared to chromosomal counterparts. Similarly, AAC(6′)-Ib efficiently acetylates in over 70% of producing Gram-negative isolates. Efflux pumps show polyspecificity; QacA preferentially binds monovalent cations like ethidium, while OqxAB accommodates diverse substrates via a flexible binding pocket, expelling fluoroquinolones at rates that elevate minimum inhibitory concentrations.

Target Modification and Protection

Plasmid-mediated target modification represents a key strategy for antibiotic resistance, where genetic elements on plasmids encode proteins that alter the structure or function of the bacterial target's , thereby preventing effective drug interaction. A prominent example is the ribosomal protection proteins, such as TetM, which are frequently carried on conjugative plasmids like those in the IncP incompatibility group. TetM binds to the and induces a conformational change that displaces from its primary on the subunit, allowing protein synthesis to resume. This mechanism confers resistance to tetracyclines by reducing the drug's inhibitory effect without degrading it or expelling it via efflux. Studies have shown that expression of plasmid-borne tetM genes can increase the (MIC) of tetracycline by 16- to 64-fold in susceptible strains, highlighting its clinical significance in pathogens like and . Similarly, plasmid-encoded qnr genes mediate quinolone resistance through target of and IV. The Qnr proteins, belonging to the pentapeptide repeat family, bind directly to these enzymes, shielding them from quinolone inhibition and maintaining fidelity. First identified on plasmids like pMG252 in , qnrA, qnrB, and qnrS variants are now widespread on multidrug resistance plasmids in . As of 2023, new plasmid-encoded qnrVc variants have been identified in environmental isolates, expanding low-level quinolone . This typically results in low-level resistance, with MIC elevations of 4- to 32-fold for , often facilitating the selection of higher-level chromosomal . Unlike enzymatic inactivation, qnr action preserves the enzyme's catalytic activity while blocking drug access. Plasmids also contribute to resistance by encoding biofilm-promoting factors, such as adhesin genes or conjugative pili components, enhance physical ; these structures create extracellular matrices that impede penetration and bacterial communities. Such mechanisms underscore plasmids' role in multifaceted beyond direct target alteration. on plasmids, particularly insertion sequences (IS), facilitate the integration and of resistance alleles, amplifying target modification strategies. IS elements like IS26 and ISCR promote the excision and insertion of resistance gene cassettes into plasmid backbones, enabling rapid . For example, IS-mediated rearrangements on IncHI2 plasmids have been linked to the acquisition of tetM alleles in , resulting in sustained high-level resistance. These elements not only drive allelic diversity but also enhance plasmid stability and transmissibility, contributing to the persistence of modified targets in bacterial populations.

Transmission and Spread

Conjugative Transfer Mechanisms

Conjugative transfer represents the primary mechanism for the horizontal dissemination of resistance plasmids among bacteria, enabling direct cell-to-cell DNA exchange through physical contact. This process is mediated by a specialized molecular apparatus encoded on the plasmid itself, which assembles a Type IV secretion system (T4SS) to form a conjugative pilus that bridges donor and recipient cells. Upon contact, the plasmid DNA is processed at its origin of transfer (oriT), where a relaxase enzyme introduces a site-specific nick, generating a single-stranded DNA molecule (T-strand) that is translocated from the donor to the recipient via the T4SS channel. In the recipient, the T-strand is circularized, replicated, and established as a functional plasmid, conferring resistance traits such as antibiotic inactivation. The core machinery for this transfer is encoded by the tra operon, a cluster of genes that direct the assembly and function of the conjugation apparatus. Key components include genes for pilin subunits (e.g., traA), which form the structure to initiate pair formation; the relaxase (e.g., traI in F-like plasmids), which catalyzes oriT nicking and covalently attaches to the 5' end of the T-strand for its delivery; and coupling proteins (e.g., traD), which recruit the relaxosome—a complex at oriT—to the T4SS for efficient export. Expression of the tra operon is tightly regulated, often through pathways that respond to bacterial population density via autoinducer molecules like N-acyl homoserine lactones, ensuring transfer occurs in favorable, high-density conditions. For instance, in , the TraR regulator activates tra genes in response to signals, linking transfer to environmental cues. Transfer efficiency is modulated by several factors that determine host range and success rates. Host range varies by plasmid incompatibility groups; for example, IncP plasmids like RP4 exhibit broad compatibility across Gram-negative species, while F plasmids are more restricted. Entry exclusion, mediated by surface proteins such as TraS and , prevents redundant transfer to recipients already harboring similar plasmids by blocking pilus receptor interactions, thereby optimizing resource use. Conjugation success typically yields 10^{-1} to 10^{-5} transconjugants per donor cell under laboratory conditions, influenced by factors like stability and T4SS functionality, with higher rates observed in optimal media. Environmental contexts significantly enhance conjugative transfer, particularly in structured microbial communities. In biofilms, close cell proximity and support increase contact frequency, boosting plasmid dissemination rates by up to several orders of magnitude compared to planktonic cells. Similarly, the anaerobic, nutrient-rich gut facilitates transfer among diverse taxa, with studies showing elevated conjugation in intestinal environments. Recent 2025 research demonstrates that stress or exposure to complex media like hospital wastewater upregulates tra genes and T4SS components (e.g., virB homologs), doubling conjugation frequencies through mechanisms such as increased and membrane permeability, thereby accelerating resistance spread under selective pressure.

Non-Conjugative Dissemination

Plasmid-mediated resistance can spread through non-conjugative mechanisms that do not require direct cell-to-cell contact, relying instead on the release and uptake of free DNA or its packaging within viral or vesicular structures. These pathways, while less efficient than conjugation, contribute to intra-species dissemination, particularly in environments where bacterial populations experience stress or high densities that promote DNA release. Transformation involves the uptake of naked plasmid DNA by naturally competent , a process observed in species such as and Acinetobacter baylyi. In these Gram-negative pathogens, competence is induced under conditions like nutrient limitation or , leading to the expression of genes for DNA binding, uptake, and integration. For instance, plasmid DNA released from lysed cells during stress can be taken up by competent A. baumannii strains, facilitating the acquisition of resistance genes such as those encoding carbapenemases. Studies have shown that A. baumannii clinical isolates exhibit , with transformation efficiencies reaching up to 10^3 transformants per microgram of plasmid DNA in laboratory assays. This mechanism supports intra-species spread in hospital settings or natural biofilms, where stress from antibiotics or host immunity triggers DNA release and uptake. Transduction occurs when bacteriophages package and transfer plasmid DNA between bacterial cells, either through generalized transduction, where random DNA fragments are incorporated into phage particles, or specialized transduction involving specific plasmid-phage interactions. In Pseudomonas aeruginosa, generalized transducing phages like φDS1 have been demonstrated to package and transfer plasmids such as Rms149, an IncP-1 incompatibility group plasmid carrying resistance determinants. This process has been observed in natural freshwater environments, where phage-mediated plasmid transfer persists over multi-day incubations, enabling dissemination among P. aeruginosa populations. Similarly, phages like F116 and D3 can transduce plasmids containing cos sites in P. aeruginosa, with the transducing particles separated from lytic ones to confirm specificity. These events highlight transduction's role in propagating resistance plasmids within Pseudomonas species in aquatic or soil habitats. Vesicle-mediated transfer utilizes outer membrane vesicles (OMVs) produced by Gram-negative bacteria to encapsulate and deliver plasmid DNA to recipient cells. OMVs, nanoscale lipid bilayers shed from the outer membrane, protect plasmid DNA from nuclease degradation and fuse with recipient membranes, allowing cytosolic entry and transformation. In A. baumannii, OMVs have transferred bla_NDM-1-carrying plasmids to both homologous and heterologous species like Escherichia coli, with transfer efficiencies enhanced by high plasmid copy numbers. P. aeruginosa OMVs similarly carry plasmids such as pAK1900, promoting resistance gene dissemination in biofilms, while E. coli OMVs facilitate interspecies plasmid exchange with pathogens like Aeromonas veronii. This pathway is particularly relevant in polymicrobial environments, where OMV production increases under stress, aiding plasmid spread without phage or direct contact. Non-conjugative dissemination generally occurs at lower frequencies than conjugation, typically ranging from 10^{-7} to 10^{-9} transductants or transformants per recipient cell, compared to conjugation rates that can reach 10^{-1} to 10^{-5} per donor. These reduced efficiencies stem from dependencies on environmental factors like DNA availability, phage multiplicity of infection, or OMV concentration, limiting widespread transfer but enabling targeted intra-species propagation in niches such as biofilms or stressed populations. Despite these constraints, such mechanisms sustain plasmid persistence by complementing conjugative spread in diverse ecological contexts.

Examples in Key Pathogens

Resistance in Enterobacteriaceae

The family encompasses clinically significant pathogens such as Escherichia coli, Klebsiella pneumoniae, and Salmonella species, which serve as primary hosts for plasmid-mediated antibiotic resistance genes. These bacteria thrive in the enteric environment of the , where dense microbial communities and nutrient-rich conditions promote frequent , resulting in elevated plasmid prevalence compared to other bacterial groups. This ecological niche facilitates the rapid acquisition and dissemination of resistance determinants, making Enterobacteriaceae a key driver of in both community and healthcare settings. In , multi-drug resistance (MDR) plasmids predominate, often encoding resistance to multiple antibiotic classes simultaneously and enabling survival in diverse selective pressures. Among incompatibility groups, IncF and IncI plasmids are especially widespread in clinical isolates, with IncF types accounting for over 60% of characterized resistance plasmids in recent genomic surveys. These plasmids' broad host range and high conjugation efficiency contribute to their dominance, allowing resistance genes to spread across species within the family. Plasmid-mediated resistance in plays a central role in hospital-acquired infections, including urinary tract infections, bloodstream infections, and , often prolonging patient stays and increasing mortality risks. Recent 2024-2025 surveillance data highlight the clinical burden, with studies reporting ESBL production in up to 60% of clinical Enterobacteriaceae isolates, the vast majority of which involve plasmid-encoded enzymes. For instance, in food-derived isolates linked to human cases, over 90% of ESBL producers carried Inc-group plasmids harboring resistance genes. Enterobacteriaceae rank among the World Health Organization's critical priority pathogens due to their plasmid-driven resistance to third-generation cephalosporins and , necessitating urgent . The international spread of these plasmids occurs prominently via food chains, where resistance from and agricultural sources contaminates produce and , facilitating transmission to humans through consumption and environmental exposure. This one-health dynamic underscores the need for integrated monitoring to curb dissemination. Specific examples of plasmid-mediated resistances, such as those to beta-lactams, exemplify these patterns in clinical contexts.

Beta-Lactam and Other Antibiotic Resistances

Plasmid-mediated resistance to beta-lactam antibiotics in primarily arises from the acquisition of bla genes, which encode extended-spectrum beta-lactamases (ESBLs) such as CTX-M and TEM variants, as well as carbapenemases like KPC and NDM. These enzymes hydrolyze the beta-lactam ring in antibiotics like penicillins, cephalosporins, and , rendering them ineffective by cleaving the bond essential for their bactericidal activity. For instance, CTX-M-15, a dominant ESBL variant, is frequently carried on conjugative plasmids such as IncF and IncI, enabling rapid dissemination among and isolates. Similarly, the blaKPC gene, encoding a serine-based carbapenemase, is often located on transferable plasmids like pKpQIL, contributing to high-level resistance against last-resort . The blaNDM-1 gene, a metallo-beta-lactamase, hydrolyzes a broad range of beta-lactams except and is mobilized via diverse plasmids, including IncA/C and IncF types, exacerbating treatment challenges in clinical settings. Quinolone resistance in is facilitated by plasmid-borne qnr genes, which encode proteins that protect and topoisomerase IV from quinolone binding, thereby reducing the drugs' ability to inhibit bacterial . Common variants like qnrA, qnrB, and qnrS are typically embedded in integrons or flanked by insertion sequences on multidrug-resistant plasmids, often co-located with other resistance determinants. Additionally, the oqxAB , encoding a multidrug , is plasmid-mediated and expels quinolones such as from the bacterial cell, lowering intracellular concentrations and conferring low- to moderate-level resistance. This efflux mechanism is prevalent in and E. coli strains, where oqxAB plasmids like pOLA are conjugative and associated with resistance to multiple quinolones. Aminoglycoside resistance is commonly mediated by plasmid-encoded genes such as aadA and aph, which are integrated into class 1 integrons and confer modification of aminoglycosides like gentamicin and streptomycin via acetylation or phosphorylation, preventing ribosomal binding. The aadA gene cassettes, often part of variable regions in integrons on broad-host-range plasmids like IncP, are highly prevalent in multidrug-resistant (MDR) Enterobacteriaceae, enabling simultaneous resistance to multiple aminoglycosides. These elements frequently co-occur with beta-lactam and quinolone resistance genes, amplifying MDR phenotypes in pathogens like Klebsiella and Enterobacter species. Clinically, plasmid-mediated resistances have driven significant outbreaks, such as the 2010 emergence of NDM-1-producing in , where blaNDM-1 on transferable plasmids like IncA/C spread rapidly among hospital patients, leading to untreatable infections and international dissemination via . By 2025, updates on resistance highlight the global rise of mcr genes, such as mcr-1 and the newly identified mcr-10, encoded on conjugative plasmids in ; these genes produce phosphoethanolamine transferases that modify in the outer membrane, reducing binding and restoring viability against this last-resort polymyxin. The mcr-9 and mcr-10 variants, often on IncHI2 and IncX3 plasmids, have been detected in increasing frequencies in clinical and environmental isolates, posing risks for pan-drug-resistant infections.

Regulatory and Evolutionary Aspects

Role of Small RNAs

Small non-coding RNAs (sRNAs) play crucial roles in regulating maintenance and stability in through interactions with toxin-antitoxin (TA) systems. In , the Sok sRNA functions as an in the type I hok/sok TA module on R1, where it base-pairs with the hok mRNA encoding a toxic , preventing its and ensuring persistence via post-segregational killing of cells that lose the . This mechanism stabilizes low-copy-number s by linking their retention to cell survival, with Sok expression tightly coupled to replication to modulate copy number indirectly. Similarly, RydC, though primarily chromosomal, exemplifies sRNA involvement in envelope homeostasis that can influence plasmid-encoded traits, but its direct role in plasmid modulation remains secondary to dedicated TA systems like Sok. In the context of antibiotic resistance, plasmid-encoded or regulated sRNAs fine-tune the expression of resistance determinants. For instance, MgrR sRNA in represses genes involved in modifications, such as pagP and eptB, thereby modulating envelope permeability and susceptibility to cationic like polymyxin B, which indirectly affects efflux efficiency. sRNAs also control s critical for multidrug resistance; in E. coli and , RyeB sRNA base-pairs with tolC mRNA to repress its translation, reducing AcrAB-TolC efflux pump assembly and increasing sensitivity to quinolones and . Regarding beta-lactam resistance, plasmid pNDM-HK carrying blaNDM-1 encodes multiple sRNAs, including pNDM-sRNA1-6, which regulate host to enhance overall fitness and persistence of resistance in . -derived sRNAs further promote bacterial persistence, as seen with stnpA, a transposon-encoded sRNA on resistance plasmids that modulates fosfomycin tolerance by altering metabolic pathways without conferring outright resistance. The primary mechanism of these sRNAs involves antisense base-pairing with target mRNAs to modulate and stability, often facilitated by the Hfq chaperone protein. In E. coli plasmids, Sok exemplifies this by binding the of hok mRNA, blocking initiation and promoting mRNA degradation, which ensures balanced TA activity for retention. This post-transcriptional control extends to resistance genes on plasmids, where sRNAs like DsrA in E. coli pair with mdtEF mRNA to activate expression, enhancing tolerance to beta-lactams and . Recent studies from the highlight sRNAs' influence on horizontal transfer efficiency of resistance . In E. coli, the GadY sRNA promotes conjugative transfer of plasmids like F by base-pairing with sdiA mRNA, derepressing the SdiA regulator to boost expression and donor-recipient mating success. Additionally, sRNAs contribute to stress responses that sustain -mediated resistance; for example, RyhB sRNA in E. coli responds to iron limitation by repressing metabolic genes, increasing persister formation and tolerance to beta-lactams and quinolones during oxidative or nutrient stress. These findings underscore sRNAs as dynamic regulators bridging stability, resistance expression, and adaptability in .

Evolution and Persistence

Plasmid-mediated resistance evolves primarily under antibiotic selection pressure, which favors the acquisition of plasmids carrying resistance genes by enhancing bacterial and proliferation in antibiotic-exposed environments. This selective force drives , allowing plasmids to disseminate rapidly among bacterial populations, particularly in clinical, agricultural, and environmental settings where antibiotics are prevalent. Recombination events further accelerate , with at core gene sites enabling the exchange of genetic modules, while insertion sequences (IS) elements promote the mobilization and integration of antibiotic resistance genes (ARGs) into plasmid backbones. These mechanisms contribute to the modular architecture of plasmids, facilitating the assembly of multi-resistance cassettes that confer adaptive advantages. Persistence of plasmids in bacterial populations is ensured through sophisticated maintenance strategies that counteract potential loss during . Toxin-antitoxin (TA) systems, such as the type II PemK/PemI module, play a critical role by inducing post-segregational killing: the stable PemI neutralizes the PemK (an mRNA endonuclease), but upon plasmid loss, the short-lived degrades, allowing PemK to inhibit growth or induce in plasmid-free cells, thereby stabilizing inheritance. Additionally, plasmids often impose fitness costs on hosts, including metabolic burdens from replication and expression of non-essential genes, which can reduce growth rates by up to 10-20% in the absence of antibiotics. However, these costs are frequently ameliorated by compensatory , either chromosomal (e.g., in global regulators like gacS) or plasmid-borne (e.g., adjustments to copy number control), enabling long-term coexistence and reducing the evolutionary barrier to plasmid retention. Mathematical models provide insights into the dynamics of plasmid invasion and persistence, simulating how plasmids spread within bacterial communities under varying selective regimes. A key metric is the basic reproduction number (R0), which integrates conjugation transfer rates, segregation loss, and antibiotic selection; when R0 > 1, plasmids can invade susceptible populations, as demonstrated in foundational models extended to account for ecological factors like population density and gene dosage effects. These simulations reveal that even parasitic plasmids can persist if horizontal transfer compensates for vertical instability, highlighting the balance between short-term costs and long-term benefits in driving resistance evolution. Global metagenomic analyses as of underscore the vast diversity of plasmid pangenomes, with over 6 million non-redundant plasmid-like clusters identified across 27 ecosystems, only a fraction of which are cataloged in public databases, revealing untapped reservoirs of ARGs enriched in mobile elements like transposases. Human-associated niches, such as the gut and , show the highest ARG abundance (up to 2.44% of plasmid genes), driven by ecological connectivity that facilitates cross-biome dissemination. Concurrently, the emergence of "superplasmids" harboring 10 or more resistance genes, exemplified by the self-transmissible pSZS128-Hv-MDR (302 kb) in , which co-carries (blaSHV-12, blaTEM-1B), quinolone (qnrB4), and other determinants alongside factors, poses escalating threats by combining multidrug resistance with enhanced transmissibility and stability.

References

  1. https://doi.org/10.1038/s41579-023-00926-x
  2. https://doi.org/10.1016/j.tim.2018.06.007
  3. https://doi.org/10.1016/S0140-6736(21)02724-0
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC12440250/
  5. https://asm.org/articles/2023/january/plasmids-and-the-spread-of-antibiotic-resistance-g
  6. https://www.nature.com/articles/s41467-024-48352-8
  7. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC2937522/
  9. https://www.nobelprize.org/prizes/medicine/1958/lederberg/facts/
  10. https://pmc.ncbi.nlm.nih.gov/articles/PMC441171/
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC8618304/
  12. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(10)70143-2/fulltext
  13. https://doi.org/10.1016/S1473-3099(13)30142-2
  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC12466860/
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC4335354/
  16. https://www.nature.com/articles/s44259-025-00145-9
  17. https://academic.oup.com/jac/article/73/5/1121/4822282
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC9008345/
  19. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2013.00044/full
  20. https://pubmed.ncbi.nlm.nih.gov/23471189/
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC11891212/
  22. https://journals.asm.org/doi/10.1128/AEM.02252-13
  23. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2016.01566/full
  24. http://pubmlst.org/organisms/plasmid-mlst
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC11701622/
  26. https://www.sciencedirect.com/science/article/pii/S0147619X2300015X
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC8284625/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC2992599/
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC4402952/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC9032748/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC8061329/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC1251510/
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC296194/
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC3479509/
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC2258611/
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC2772364/
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC4288778/
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC151764/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC2612276/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC11107853/
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC9484755/
  42. https://pmc.ncbi.nlm.nih.gov/articles/PMC10294622/
  43. https://pubmed.ncbi.nlm.nih.gov/33526659/
  44. https://doi.org/10.3390/genes11111239
  45. https://doi.org/10.1146/annurev.micro.58.030603.123630
  46. https://doi.org/10.1074/jbc.M008728200
  47. https://doi.org/10.1111/j.1365-2958.2008.06391.x
  48. https://doi.org/10.3389/fcimb.2017.00007
  49. https://doi.org/10.1016/S0378-1097(03)00430-0
  50. https://doi.org/10.1099/mic.0.2006/001917-0
  51. https://doi.org/10.1128/AEM.65.8.3710-3713.1999
  52. https://doi.org/10.1046/j.1462-2920.2003.00459.x
  53. https://doi.org/10.3389/fmicb.2025.1626123
  54. https://www.sciencedirect.com/science/article/pii/S1369527421001284
  55. https://www.nature.com/articles/ismej201535
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC2849597/
  57. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.738034/full
  58. https://pmc.ncbi.nlm.nih.gov/articles/PMC203799/
  59. https://journals.asm.org/doi/10.1128/jb.172.6.3509-3511.1990
  60. https://pmc.ncbi.nlm.nih.gov/articles/PMC243129/
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC8198371/
  62. https://academic.oup.com/jac/article/72/8/2201/3823277
  63. https://journals.asm.org/doi/10.1128/spectrum.05179-22
  64. https://doi.org/10.1111/j.1574-6941.2002.tb01008.x
  65. https://doi.org/10.1016/j.ijheh.2019.01.004
  66. https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.001453
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC11622690/
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC12388533/
  69. https://www.who.int/publications/i/item/9789240093461
  70. https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000858
  71. https://www.sciencedirect.com/science/article/pii/S235277142500309X
  72. https://academic.oup.com/jacamr/article/3/3/dlab092/6322891
  73. https://pmc.ncbi.nlm.nih.gov/articles/PMC9854900/
  74. https://www.mdpi.com/2227-9059/11/11/2937
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC7168674/
  76. https://www.thelancet.com/article/S1473-3099%2810%2970143-2/fulltext
  77. https://pubmed.ncbi.nlm.nih.gov/27889879/
  78. https://journals.asm.org/doi/10.1128/microbiolspec.plas-0006-2013
  79. https://academic.oup.com/jac/article/68/1/68/673963
  80. https://aricjournal.biomedcentral.com/articles/10.1186/s13756-019-0489-3
  81. https://www.nature.com/articles/s44259-023-00014-3
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC3394789/
  83. https://pmc.ncbi.nlm.nih.gov/articles/PMC12561702/
  84. https://www.nature.com/articles/s43856-025-01109-w
  85. https://link.springer.com/article/10.1007/s11084-025-09706-4
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC4147584/
  87. https://theses.hal.science/tel-02275785/file/MASACHIS_GELO_SARA_2018_RED.pdf
  88. https://pmc.ncbi.nlm.nih.gov/articles/PMC4337610/
  89. https://pmc.ncbi.nlm.nih.gov/articles/PMC5418344/
  90. https://www.jmicrobiol.or.kr/journal/view.php?doi=10.71150/jm.2501027
  91. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.00532/full
  92. https://journals.asm.org/doi/10.1128/mbio.03814-24
  93. https://pmc.ncbi.nlm.nih.gov/articles/PMC11300174/
Add your contribution
Related Hubs
User Avatar
No comments yet.