RelA Mutant
            <i>Enterococcus faecium</i>
            with Multiantibiotic Tolerance Arising in an Immunocompromised Host

Honsa, Erin S.; Cooper, Vaughn S.; Mhaissen, Mohammed N.; Frank, Matthew W.; Shaker, Jessica; Iverson, Amy; Rubnitz, Jeffrey E.; Hayden, Randall T.; Lee, Richard; Rock, Charles O.; Tuomanen, Elaine; Wolf, Joshua; Rosch, Jason W.

doi:10.1128/mbio.02124-16

Cited by 85 publications

(83 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Bacterial pathogens evolve during infection as they adapt to the environment inside the host (1). Since the bacterial phenotypes selected in vivo may have profound impact on disease severity and progression (2, 3) as well as response to antibiotic therapy (4), identification and analysis of the full range of beneficial genetic changes that underlies host adaptation is of importance.…”

Section: Introductionmentioning

confidence: 99%

Host adaptation mediated by intergenic evolution in a bacterial pathogen

Khademi

Jelsbak

2017

Preprint

View full text Add to dashboard Cite

Bacterial pathogens evolve during the course of infection as they adapt to the selective pressures that confront them inside the host. Identification of adaptive mutations and their contributions to pathogen fitness remain a central challenge. Although mutations can either target intergenic or coding regions in the pathogen genome, studies of host adaptation have focused predominantly on molecular evolution within coding regions, whereas the role of intergenic mutations remains unclear. Here, we address this issue and investigate the extent to which intergenic mutations contribute to the evolutionary response of pathogens to host environments, and whether intergenic mutations have distinct roles in host adaptation. We characterize intergenic evolution in 44 lineages of a clinically important bacterial pathogen, Pseudomonas aeruginosa, as they adapt to their hosts. We identify 88 intergenic regions in which parallel evolution occurs. At the genetic level, we find that mutations in these regions under selection are located primarily within regulatory elements upstream of transcriptional start sites. At the functional level, we show that these mutations both create or destroy regulatory interactions in connection to transcriptional processes and are directly responsible for evolution of important pathogenic phenotypes including antibiotic sensitivity. Importantly, we find that intergenic mutations are more likely to be selected than coding region mutations and that intergenic mutations enable essential genes to become targets of evolution. In summary, our results highlight the evolutionary significance of intergenic mutations in creating host-adapted variants and that intergenic and coding regions have different qualitative and quantitative contributions to this process.SignificancePathogens adapt to their host during infection, but the contribution and function of non-coding intergenic sequences to adaptation is poorly understood. Here, genome-wide identification of adaptive mutations within intergenic regions demonstrates that these sequences constitute an important part of the genetic basis for host adaptation. We find that intergenic mutations are abundant relative to adaptive mutations within coding sequences, and can contribute directly to evolution of pathogen-relevant traits. Importantly, we find that intergenic mutations modify expression of essential genes and thus make contributions that are functionally distinct from coding mutations. These results improve our understanding of the evolutionary processes in vivo and can potentially assist in refining predictions of pathogen evolution, disease outcome and antibiotic resistance development.

show abstract

Section: Introductionmentioning

confidence: 99%

Host adaptation mediated by intergenic evolution in a bacterial pathogen

Khademi

Jelsbak

2017

Preprint

View full text Add to dashboard Cite

show abstract

“…Changes in ppGpp concentration modulate the stringent stress response and impact antibiotic tolerance and virulence in Enterococcus (45, 46). Mutations in relA have previously been associated with in vitro (47) and in vivo (48) emergence of DAP resistance in Bacillus subtilis and E. faecium , respectively. In DAP-A1, deletion of 11 bases (CTAGGATTTAC) from relA results in synthesis of a truncated, 505 amino acid protein that lacks the C-terminal ACT regulatory domain.…”

Section: Resultsmentioning

confidence: 99%

Reduced chlorhexidine and daptomycin susceptibility arises in vancomycin-resistantEnterococcus faeciumafter serial chlorhexidine exposure

Bhardwaj¹,

Hans²,

Ruikar³

et al. 2017

Preprint

View full text Add to dashboard Cite

Vancomycin-resistant Enterococcus faecium (VREfm) are critical public health concerns because they are among the leading causes of hospital-acquired bloodstream infections. Chlorhexidine (CHX) is a bisbiguanide cationic antiseptic that is routinely used for patient bathing and other infection control practices. VREfm are likely frequently exposed to CHX; however, the long-term effects of CHX exposure have not been studied in enterococci. In this study, we serially exposed VREfm to increasing concentrations of CHX for a period of 21 days in two independent experimental evolution trials. Reduced CHX susceptibility emerged (4-fold shift in CHX MIC). Sub-populations with reduced daptomycin (DAP) susceptibility were detected, which were further analyzed by genome sequencing and lipidomic analysis. Across the trials, we identified adaptive changes in genes with predicted or experimentally confirmed roles in chlorhexidine susceptibility (efrE), global nutritional stress response (relA), nucleotide metabolism (cmk), phosphate acquisition (phoU), and glycolipid biosynthesis (bgsB), among others. Moreover, significant alterations in membrane phospholipids were identified. Our results are clinically significant because they identify a link between serial sub-inhibitory CHX exposure and reduced DAP susceptibility. In addition, the CHX-induced genetic and lipidomic changes described in this study offer new insights into the mechanisms underlying the emergence of antibiotic resistance in VREfm.

show abstract

“…Therefore, at least in B. subtilis , (p)ppGpp is a key inducer of persister generation and a modulator of persister dynamics. We suspect that (p)ppGpp also plays similar roles in persister generation in multiple pathogens, since mutants with elevated (p)ppGpp levels have been isolated from patients with recurrent infections after antibiotic treatments (Berti et al, 2018; Gao et al, 2010; Honsa et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

A shared alarmone-GTP switch underlies triggered and spontaneous persistence

Fung

Barra

Schroeder

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryPhenotypically-switched, antibiotic-refractory persisters may prevent pathogen eradication. Although how triggered persistence via starvation-induced (p)ppGpp is well characterized, generation of persisters without starvation are poorly understood. Here we visualized the formation of spontaneous persisters in a small fraction of cells from growing wild type bacteria, revealing a striking single cell rapid switch from growth to dormancy. This switch-like entrance is triggered by GTP dropping beneath a threshold due to stochastic production and self-amplification of (p)ppGpp via allosteric enzyme activation. In addition, persisters are induced by lethal and sublethal concentrations of cell wall antibiotics by inducing (p)ppGpp via cell wall stress response. Thus spontaneous, triggered and antibiotic-induced persisters can all stem from a common metabolic switch: GTP depletion by (p)ppGpp induction, and each pathway of persister formation is activated by different (p)ppGpp synthetases. These persistence pathways are likely conserved in pathogens which may be exploited to potentiate antibiotic efficacy.

show abstract

RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host

Cited by 85 publications

References 53 publications

Host adaptation mediated by intergenic evolution in a bacterial pathogen

Host adaptation mediated by intergenic evolution in a bacterial pathogen

Reduced chlorhexidine and daptomycin susceptibility arises in vancomycin-resistantEnterococcus faeciumafter serial chlorhexidine exposure

A shared alarmone-GTP switch underlies triggered and spontaneous persistence

Contact Info

Product

Resources

About