The rise of the Enterococcus: beyond vancomycin resistance

Arias, César A.; Murray, Barbara E.

doi:10.1038/nrmicro2761

Cited by 1,363 publications

(1,283 citation statements)

References 153 publications

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“…11 Enterococci are intrinsically resistant to many antimicrobials, but also easily acquire mutations and exogenous genes to develop further resistance. 56 While aminopenicillin resistance is rare (<1%) to low (up to 25%) in E. faecalis, it is encountered around 90 % of nosocomial E. faecium isolates. 17,56 Beta-lactamase production is infrequently associated with resistance and can be overcome with the use of b-lactamase inhibitor compounds.…”

Section: Gram-positive Bacteriamentioning

confidence: 99%

“…56 While aminopenicillin resistance is rare (<1%) to low (up to 25%) in E. faecalis, it is encountered around 90 % of nosocomial E. faecium isolates. 17,56 Beta-lactamase production is infrequently associated with resistance and can be overcome with the use of b-lactamase inhibitor compounds. The production of PBP5 with low affinity to penicillins is the major culprit for b-lactam resistance.…”

Section: Gram-positive Bacteriamentioning

confidence: 99%

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Epidemiology of antimicrobial resistance in bloodstream infections

2016

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Antimicrobial resistance in bacterial pathogens is a worldwide challenge leading high morbidity and mortality in clinical settings. Multidrug resistant patterns in gram-positive and -negative bacteria have resulted in difficult-to-treat or even untreatable infections with conventional antimicrobials. Since the early identification of causative microorganisms and their antimicrobial susceptibility patterns in patients with bacteremia and other serious infections is lacking in many healthcare institutions, broad spectrum antibiotics are liberally and mostly unnecessarily used. Such practice has, in turn, caused dramatic increases in emerging resistance and when coupled with poor practice of infection control, resistant bacteria can easily be disseminated to the other patients and the environment. Thus, availability of updated epidemiological data on antimicrobial resistance in frequently encountered bacterial pathogens will be useful not only for deciding on empirical treatment strategies, but also devising an effective antimicrobial stewardship program in hospitals.

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Section: Gram-positive Bacteriamentioning

confidence: 99%

Section: Gram-positive Bacteriamentioning

confidence: 99%

Epidemiology of antimicrobial resistance in bloodstream infections

2016

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“…The dual life style of E. faecalis relies primarily on remarkable capacities to face and survive in harsh environmental conditions. [1][2][3] We previously reported a peculiar chromosomal locus (coined hereafter TAI-II locus) containing 2 adjacent putative toxin-antitoxin (TA) modules, organized in an antisense orientation and predicted to belong to type I (txpA-ratA) and type II (mazEF) families in the clinical E. faecalis isolate V583 (Fig. 1A).…”

Section: Introductionmentioning

confidence: 99%

Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis

et al. 2015

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We discovered a chromosomal locus containing 2 toxin-antitoxin modules (TAs) with an antisense transcriptional organization in the E. faecalis clinical isolate V583. These TAs are homologous to the type I txpA-ratA system and the type II mazEF, respectively. We have shown that the putative MazF is toxic for E. coli and triggers RNA degradation, and its cognate antitoxin MazE counteracts toxicity. The second module, adjacent to mazEF, expresses a toxin predicted to belong to the TxpA type I family found in Firmicutes, and the antisense RNA antidote, RatA. Genomic analysis indicates that the cis-association of mazEF and txpA-ratA modules has been favored during evolution, suggesting a selective advantage for this TA organization in the E. faecalis species. We showed regulatory interplays between the 2 modules, involving transcription control and RNA stability. Remarkably, our data reveal that MazE and MazEF have a dual transcriptional activity: they act as autorepressors and activate ratA transcription, most likely in a direct manner. RatA controls txpA RNA levels through stability. Our data suggest a pivotal role of MazEF in the coordinated expression of mazEF and txpA-ratA modules in V583. To our knowledge, this is the first report describing a crosstalk between type I and II TAs.

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“…E nterococcus faecalis is a common member of the human gut microbiota but also a leading cause of a number of hospital-acquired infections such as endocarditis and surgical wound and urinary tract infections (1). The association of this opportunistic pathogen with disease relies on its exceptional resilience, which allows it to prevail in the unfavorable hospital setting while providing a competitive advantage over other bacteria during both infection and treatment.…”

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confidence: 99%

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

2017

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In Enterococcus faecalis, the regulatory nucleotides pppGpp and ppGpp, collectively, (p)ppGpp, are required for growth in blood, survival within macrophages, and virulence. However, a clear understanding of how (p)ppGpp promotes virulence in E. faecalis and other bacterial pathogens is still lacking. In the host, the essential transition metals iron (Fe) and manganese (Mn) are not readily available to invading pathogens because of a host-driven process called nutritional immunity. Considering its central role in adaptation to nutritional stresses, we hypothesized that (p)ppGpp mediates E. faecalis virulence through regulation of metal homeostasis. Indeed, supplementation of serum with either Fe or Mn restored growth and survival of the Δrel ΔrelQ [(p)ppGpp 0 ] strain to wild-type levels. Using a chemically defined medium, we found that (p)ppGpp accumulates in response to either Fe depletion or Mn depletion and that the (p)ppGpp 0 strain has a strong growth requirement for Mn that is alleviated by Fe supplementation. Although inactivation of the nutrient-sensing regulator codY restored some phenotypes of the (p)ppGpp 0 strain, transcriptional analysis showed that the (p)ppGpp/CodY network does not promote transcription of known metal transporters. Interestingly, physiologic and enzymatic investigations suggest that the (p)ppGpp 0 strain requires higher levels of Mn in order to cope with high levels of endogenously produced reactive oxygen species (ROS). Because (p)ppGpp mediates antibiotic persistence and virulence in several bacteria, our findings have broad implications and provide new leads for the development of novel therapeutic and preventive strategies against E. faecalis and beyond. KEYWORDS (p)ppGpp, Enterococcus, manganese, metal homeostasis, nutritional immunity, oxidative stress E nterococcus faecalis is a common member of the human gut microbiota but also a leading cause of a number of hospital-acquired infections such as endocarditis and surgical wound and urinary tract infections (1). The association of this opportunistic pathogen with disease relies on its exceptional resilience, which allows it to prevail in the unfavorable hospital setting while providing a competitive advantage over other bacteria during both infection and treatment.Among the most prominent regulators involved in bacterial adaptation to stress are the nucleotide second messengers guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), collectively, (p)ppGpp, best known as the effectors of the stringent response (SR) (2). While initially discovered to accumulate in response to amino acid starvation, (p)ppGpp has also been shown to accumulate in response to restrictions in carbon, fatty acids, and iron, as well as in response to other nonnutritional stresses (3). During the SR, (p)ppGpp accumulation triggers transcriptional alterations that lead to general repression of rapid growth and simultaneous activation of stress survival, nutrient uptake, and biosynthesis pathways. In addition to its involvement in...

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The rise of the Enterococcus: beyond vancomycin resistance

Cited by 1,363 publications

References 153 publications

Epidemiology of antimicrobial resistance in bloodstream infections

Epidemiology of antimicrobial resistance in bloodstream infections

Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

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