RelA Mutant <italic toggle="yes">Enterococcus faecium</italic> with Multiantibiotic Tolerance Arising in an Immunocompromised Host
ABSTRACT Serious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomyc...
Guardado en:
| Autores principales: | , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
American Society for Microbiology
2017
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/51449a358212457e9988f89c165e7419 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:51449a358212457e9988f89c165e7419 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:51449a358212457e9988f89c165e74192021-11-15T15:51:06ZRelA Mutant <italic toggle="yes">Enterococcus faecium</italic> with Multiantibiotic Tolerance Arising in an Immunocompromised Host10.1128/mBio.02124-162150-7511https://doaj.org/article/51449a358212457e9988f89c165e74192017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02124-16https://doaj.org/toc/2150-7511ABSTRACT Serious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomycin-resistant Enterococcus faecium (VRE) bacteremia that persisted for 26 days despite appropriate antibiotic therapy. Sequencing of 22 consecutive VRE isolates identified the emergence of a single missense mutation (L152F) in relA, which constitutively activated the stringent response, resulting in elevated baseline levels of the alarmone guanosine tetraphosphate (ppGpp). Although the mutant remained susceptible to both linezolid and daptomycin in clinical MIC testing and during planktonic growth, it demonstrated tolerance to high doses of both antibiotics when growing in a biofilm. This biofilm-specific gain in resistance was reflected in the broad shift in transcript levels caused by the mutation. Only an experimental biofilm-targeting ClpP-activating antibiotic was able to kill the mutant strain in an established biofilm. The relA mutation was associated with a fitness trade-off, forming smaller and less-well-populated biofilms on biological surfaces. We conclude that clinically relevant relA mutations can emerge during prolonged VRE infection, causing baseline activation of the stringent response, subsequent antibiotic tolerance, and delayed eradication in an immunocompromised state. IMPORTANCE The increasing prevalence of antibiotic-resistant bacterial pathogens is a major challenge currently facing the medical community. Such pathogens are of particular importance in immunocompromised patients as these individuals may favor emergence of novel resistance determinants due to lack of innate immune defenses and intensive antibiotic exposure. During the course of chemotherapy, a patient developed prolonged bacteremia with vancomycin-resistant Enterococcus faecium that failed to clear despite multiple front-line antibiotics. The consecutive bloodstream isolates were sequenced, and a single missense mutation identified in the relA gene, the mediator of the stringent response. Strains harboring the mutation had elevated baseline levels of the alarmone and displayed heightened resistance to the bactericidal activity of multiple antibiotics, particularly in a biofilm. Using a new class of compounds that modulate ClpP activity, the biofilms were successfully eradicated. These data represent the first clinical emergence of mutations in the stringent response in vancomycin-resistant entereococci.Erin S. HonsaVaughn S. CooperMohammed N. MhaissenMatthew FrankJessica ShakerAmy IversonJeffrey RubnitzRandall T. HaydenRichard E. LeeCharles O. RockElaine I. TuomanenJoshua WolfJason W. RoschAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Microbiology QR1-502 |
| spellingShingle |
Microbiology QR1-502 Erin S. Honsa Vaughn S. Cooper Mohammed N. Mhaissen Matthew Frank Jessica Shaker Amy Iverson Jeffrey Rubnitz Randall T. Hayden Richard E. Lee Charles O. Rock Elaine I. Tuomanen Joshua Wolf Jason W. Rosch RelA Mutant <italic toggle="yes">Enterococcus faecium</italic> with Multiantibiotic Tolerance Arising in an Immunocompromised Host |
| description |
ABSTRACT Serious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomycin-resistant Enterococcus faecium (VRE) bacteremia that persisted for 26 days despite appropriate antibiotic therapy. Sequencing of 22 consecutive VRE isolates identified the emergence of a single missense mutation (L152F) in relA, which constitutively activated the stringent response, resulting in elevated baseline levels of the alarmone guanosine tetraphosphate (ppGpp). Although the mutant remained susceptible to both linezolid and daptomycin in clinical MIC testing and during planktonic growth, it demonstrated tolerance to high doses of both antibiotics when growing in a biofilm. This biofilm-specific gain in resistance was reflected in the broad shift in transcript levels caused by the mutation. Only an experimental biofilm-targeting ClpP-activating antibiotic was able to kill the mutant strain in an established biofilm. The relA mutation was associated with a fitness trade-off, forming smaller and less-well-populated biofilms on biological surfaces. We conclude that clinically relevant relA mutations can emerge during prolonged VRE infection, causing baseline activation of the stringent response, subsequent antibiotic tolerance, and delayed eradication in an immunocompromised state. IMPORTANCE The increasing prevalence of antibiotic-resistant bacterial pathogens is a major challenge currently facing the medical community. Such pathogens are of particular importance in immunocompromised patients as these individuals may favor emergence of novel resistance determinants due to lack of innate immune defenses and intensive antibiotic exposure. During the course of chemotherapy, a patient developed prolonged bacteremia with vancomycin-resistant Enterococcus faecium that failed to clear despite multiple front-line antibiotics. The consecutive bloodstream isolates were sequenced, and a single missense mutation identified in the relA gene, the mediator of the stringent response. Strains harboring the mutation had elevated baseline levels of the alarmone and displayed heightened resistance to the bactericidal activity of multiple antibiotics, particularly in a biofilm. Using a new class of compounds that modulate ClpP activity, the biofilms were successfully eradicated. These data represent the first clinical emergence of mutations in the stringent response in vancomycin-resistant entereococci. |
| format |
article |
| author |
Erin S. Honsa Vaughn S. Cooper Mohammed N. Mhaissen Matthew Frank Jessica Shaker Amy Iverson Jeffrey Rubnitz Randall T. Hayden Richard E. Lee Charles O. Rock Elaine I. Tuomanen Joshua Wolf Jason W. Rosch |
| author_facet |
Erin S. Honsa Vaughn S. Cooper Mohammed N. Mhaissen Matthew Frank Jessica Shaker Amy Iverson Jeffrey Rubnitz Randall T. Hayden Richard E. Lee Charles O. Rock Elaine I. Tuomanen Joshua Wolf Jason W. Rosch |
| author_sort |
Erin S. Honsa |
| title |
RelA Mutant <italic toggle="yes">Enterococcus faecium</italic> with Multiantibiotic Tolerance Arising in an Immunocompromised Host |
| title_short |
RelA Mutant <italic toggle="yes">Enterococcus faecium</italic> with Multiantibiotic Tolerance Arising in an Immunocompromised Host |
| title_full |
RelA Mutant <italic toggle="yes">Enterococcus faecium</italic> with Multiantibiotic Tolerance Arising in an Immunocompromised Host |
| title_fullStr |
RelA Mutant <italic toggle="yes">Enterococcus faecium</italic> with Multiantibiotic Tolerance Arising in an Immunocompromised Host |
| title_full_unstemmed |
RelA Mutant <italic toggle="yes">Enterococcus faecium</italic> with Multiantibiotic Tolerance Arising in an Immunocompromised Host |
| title_sort |
rela mutant <italic toggle="yes">enterococcus faecium</italic> with multiantibiotic tolerance arising in an immunocompromised host |
| publisher |
American Society for Microbiology |
| publishDate |
2017 |
| url |
https://doaj.org/article/51449a358212457e9988f89c165e7419 |
| work_keys_str_mv |
AT erinshonsa relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT vaughnscooper relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT mohammednmhaissen relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT matthewfrank relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT jessicashaker relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT amyiverson relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT jeffreyrubnitz relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT randallthayden relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT richardelee relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT charlesorock relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT elaineituomanen relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT joshuawolf relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost AT jasonwrosch relamutantitalictoggleyesenterococcusfaeciumitalicwithmultiantibiotictolerancearisinginanimmunocompromisedhost |
| _version_ |
1718427397374607360 |