Extensive DNA mimicry by the ArdA anti-restriction protein and its role in the spread of antibiotic resistance

McMahon, S.A.; Roberts, Gareth A.; Johnson, Kenneth A.; Cooper, Laurie P.; Liu, Huanting; White, John H.; Carter, Lester G.; Sanghvi, Bansi; Oke, M.; Walkinshaw, Malcolm D.; Blakely, Garry W.; Naismith, James H.; Dryden, David T. F.

doi:10.1093/nar/gkp478

Cited by 107 publications

(122 citation statements)

References 73 publications

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“…Activities of the EfaRFI system against singlestranded DNA and hemimethylated DNA are as yet unknown, and further studies will be required to assess its spectrum of biochemical activities. We note also that pCF10 harbors genes for a predicted ArdA protein within a Tn925 element and that ArdA proteins inhibit type I REases by acting as a DNA mimic (71)(72)(73)(74). Whether the pCF10 ArdA has any impact on EfaRFI, a type II system, remains to be determined.…”

Section: Discussionmentioning

confidence: 91%

Genome Modification in Enterococcus faecalis OG1RF Assessed by Bisulfite Sequencing and Single-Molecule Real-Time Sequencing

et al. 2015

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Enterococcus faecalis is a Gram-positive bacterium that natively colonizes the human gastrointestinal tract and opportunistically causes life-threatening infections. Multidrug-resistant (MDR) E. faecalis strains have emerged, reducing treatment options for these infections. MDR E. faecalis strains have large genomes containing mobile genetic elements (MGEs) that harbor genes for antibiotic resistance and virulence determinants. Bacteria commonly possess genome defense mechanisms to block MGE acquisition, and we hypothesize that these mechanisms have been compromised in MDR E. faecalis. In restriction-modification (R-M) defense, the bacterial genome is methylated at cytosine (C) or adenine (A) residues by a methyltransferase (MTase), such that nonself DNA can be distinguished from self DNA. A cognate restriction endonuclease digests improperly modified nonself DNA. Little is known about R-M in E. faecalis. Here, we use genome resequencing to identify DNA modifications occurring in the oral isolate OG1RF. OG1RF has one of the smallest E. faecalis genomes sequenced to date and possesses few MGEs. Single-molecule real-time (SMRT) and bisulfite sequencing revealed that OG1RF has global 5-methylcytosine (m5C) methylation at 5=-GC-WGC-3= motifs. A type II R-M system confers the m5C modification, and disruption of this system impacts OG1RF electrotransformability and conjugative transfer of an antibiotic resistance plasmid. A second DNA MTase was poorly expressed under laboratory conditions but conferred global N 4 -methylcytosine (m4C) methylation at 5=-CCGG-3= motifs when expressed in Escherichia coli. Based on our results, we conclude that R-M can act as a barrier to MGE acquisition and likely influences antibiotic resistance gene dissemination in the E. faecalis species. IMPORTANCEThe horizontal transfer of antibiotic resistance genes among bacteria is a critical public health concern. Enterococcus faecalis is an opportunistic pathogen that causes life-threatening infections in humans. Multidrug resistance acquired by horizontal gene transfer limits treatment options for these infections. In this study, we used innovative DNA sequencing methodologies to investigate how a model strain of E. faecalis discriminates its own DNA from foreign DNA, i.e., self versus nonself discrimination. We also assess the role of an E. faecalis genome modification system in modulating conjugative transfer of an antibiotic resistance plasmid. These results are significant because they demonstrate that differential genome modification impacts horizontal gene transfer frequencies in E. faecalis. Enterococcus faecalis is a Gram-positive bacterium that natively colonizes the gastrointestinal tracts of humans and other animals (1). It is an opportunistic pathogen that causes life-threatening infections, such as bacteremia and endocarditis in compromised individuals (2). E. faecalis is among the leading causes of hospital-acquired infections in the United States, making it a major public health concern (3). Rising antibiotic resistance...

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Section: Discussionmentioning

confidence: 91%

Genome Modification in Enterococcus faecalis OG1RF Assessed by Bisulfite Sequencing and Single-Molecule Real-Time Sequencing

et al. 2015

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“…Similar DNA mimics, termed Ard (alleviation of restriction of DNA) proteins, are expressed by many plasmids. To illustrate, ArdA, which is rich in Asp and Glu residues, mimics a 42-bp DNA and inhibits type I enzymes (63). In addition, some of the phages and conjugating plasmids are known to encode antirestriction proteins, which alleviate the restriction function (26).…”

Section: Strategies Against R-m Systemsmentioning

confidence: 99%

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

Vasu

Nagaraja

2013

Microbiol Mol Biol Rev

509

462

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SUMMARY Restriction-modification (R-M) systems are ubiquitous and are often considered primitive immune systems in bacteria. Their diversity and prevalence across the prokaryotic kingdom are an indication of their success as a defense mechanism against invading genomes. However, their cellular defense function does not adequately explain the basis for their immaculate specificity in sequence recognition and nonuniform distribution, ranging from none to too many, in diverse species. The present review deals with new developments which provide insights into the roles of these enzymes in other aspects of cellular function. In this review, emphasis is placed on novel hypotheses and various findings that have not yet been dealt with in a critical review. Emerging studies indicate their role in various cellular processes other than host defense, virulence, and even controlling the rate of evolution of the organism. We also discuss how R-M systems could have successfully evolved and be involved in additional cellular portfolios, thereby increasing the relative fitness of their hosts in the population.

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“…A well-known example of such a protein is the "overcome classical restriction" (OCR) protein encoded by T7 phages (219), which binds to type I RM systems by mimicking B-form DNA to prevent cleavage activity. Similar types of mimicking proteins, named "alleviation of restriction of DNA" (Ard) proteins, are encoded by a range of plasmids, and these proteins also inhibit type I enzymes (220). Selection on phage genomes to evade restriction has led to restriction site avoidance in the phage genome (221).…”

Section: Figmentioning

confidence: 99%

Evolutionary Ecology of Prokaryotic Immune Mechanisms

Houte

Buckling

Westra

2016

Microbiol Mol Biol Rev

215

177

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SUMMARYBacteria have a range of distinct immune strategies that provide protection against bacteriophage (phage) infections. While much has been learned about the mechanism of action of these defense strategies, it is less clear why such diversity in defense strategies has evolved. In this review, we discuss the short- and long-term costs and benefits of the different resistance strategies and, hence, the ecological conditions that are likely to favor the different strategies alone and in combination. Finally, we discuss some of the broader consequences, beyond resistance to phage and other genetic elements, resulting from the operation of different immune strategies.

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Extensive DNA mimicry by the ArdA anti-restriction protein and its role in the spread of antibiotic resistance

Cited by 107 publications

References 73 publications

Genome Modification in Enterococcus faecalis OG1RF Assessed by Bisulfite Sequencing and Single-Molecule Real-Time Sequencing

Genome Modification in Enterococcus faecalis OG1RF Assessed by Bisulfite Sequencing and Single-Molecule Real-Time Sequencing

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

Evolutionary Ecology of Prokaryotic Immune Mechanisms

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