Secondary Cell Wall Polymers of Enterococcus faecalis Are Critical for Resistance to Complement Activation via Mannose-binding Lectin

Geiss-Liebisch, Stefan; Rooijakkers, Suzan H. M.; Beczała, Agnieszka; Sanchéz-Carballo, Patricia; Kruszynska, Karolina; Repp, Christian; Sakinc, Tuerkan; Vinogradov, Evgeny; Holst, Otto; Hüebner, Johannes; Theilacker, Christian

doi:10.1074/jbc.m112.358283

Cited by 50 publications

(42 citation statements)

References 51 publications

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“…Bacterial surface polysaccharides directly interact with mammalian host surfaces and are key virulence factors (17, 34, 37-41). Previous studies identified glucose, rhamnose, N -acetylglucosamine, N -acetyl galactosamine, and galactose as major components of Epa (17, 34); however, there are gaps in our understanding of the Epa cell surface architecture.…”

Section: Discussionmentioning

confidence: 99%

Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci

Chatterjee

Johnson

Luong

et al. 2019

Preprint

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27Enterococcus faecalis is a human intestinal pathobiont with intrinsic and acquired resistance to 28 many antibiotics, including vancomycin. Nature provides a diverse and virtually untapped repertoire of 29 bacterial viruses, or bacteriophages (phages), that could be harnessed to combat multi-drug resistant 30 enterococcal infections. Bacterial phage resistance represents a potential barrier to the implementation 31 of phage therapy, emphasizing the importance of investigating the molecular mechanisms underlying the 32 emergence of phage resistance. Using a cohort of 19 environmental lytic phages with tropism against E. 33 faecalis, we found that these phages require the enterococcal polysaccharide antigen (Epa) for 34 productive infection. Epa is a surface-exposed heteroglycan synthesized by enzymes encoded by both 35 conserved and strain specific genes. We discovered that exposure to phage selective pressure favors 36 mutation in non-conserved epa genes both in culture and in a mouse model of intestinal colonization. 37Despite gaining phage resistance, epa mutant strains exhibited a loss of resistance to the cell wall 38 targeting antibiotics, vancomycin and daptomycin. Finally, we show that an E. faecalis epa mutant strain 39 is deficient in intestinal colonization, cannot expand its population upon antibiotic-driven intestinal 40 dysbiosis and fails to be efficiently transmitted to juvenile mice following birth. This study demonstrates 41 that phage therapy could be used in combination with antibiotics to target enterococci within a dysbiotic 42 microbiota. Enterococci that evade phage therapy by developing resistance may be less fit at colonizing 43 the intestine and sensitized to vancomycin preventing their overgrowth during antibiotic treatment. 44 45 Importance 46With the continued rise of multidrug resistant bacteria, it is imperative that new therapeutic options 47 are explored. Bacteriophages (phages) hold promise for the amelioration of enterococcal infections, 48 however, the mechanisms used by enterococci to subvert phage infection are understudied. Here, we 49 demonstrate that a collection of phages require a cell surface exopolysaccharide for infection of E. 50faecalis. E. faecalis develops phage resistance by mutating polysaccharide biosynthesis genes at a cost, 51 as this renders the bacterium more susceptible to cell wall targeting antibiotics. E. faecalis phage resistant 52 3 isolates are also less fit at colonizing the intestine and these mutations mitigate E. faecalis intestinal 53 expansion upon antibiotic selection. This study suggests that the emergence of phage resistance may 54 not always hinder the efficacy of phage therapy and that the use of phages may sensitize bacteria to 55 antibiotics. This could serve as a promising avenue for phage-antibiotic combination therapies. 56 57 Introduction 58 Enterococci are Gram-positive commensal bacteria native to the intestinal tracts of animals, 59 including humans (1). Under healthy conditions, enterococci exist as minority members of the micr...

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Section: Discussionmentioning

confidence: 99%

Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci

Chatterjee

Johnson

Luong

et al. 2019

Preprint

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“…WTAs have a very complex structure, which is distinct from that of S. aureus or Listeria. Of note, E. faecalis or E. faecium produce different WTAs with hexose-containing repeating units (GalNAc-RboP glycosylated with ␣-linked rhamnose or Glc-GalNAc-RboP glycosylated with ␣-linked Glc, both WTAs found in E. faecalis V583 whereas non-substituted GalNAc-GroP, type WTA was found in E. faecium U0317) (Bychowska et al, 2011;Geiss-Liebisch et al, 2012) (Table 1). Although some functions of Enterococcus WTAs including evasion from the lectin pathways of the human complement system have recently been described (Geiss-Liebisch et al, 2012) it still has to be elucidated how and why enterococci glycosylate their WTA.…”

Section: Role Of Wta Glycosylation In Other Gram-positive Bacteriamentioning

confidence: 99%

“…Of note, E. faecalis or E. faecium produce different WTAs with hexose-containing repeating units (GalNAc-RboP glycosylated with ␣-linked rhamnose or Glc-GalNAc-RboP glycosylated with ␣-linked Glc, both WTAs found in E. faecalis V583 whereas non-substituted GalNAc-GroP, type WTA was found in E. faecium U0317) (Bychowska et al, 2011;Geiss-Liebisch et al, 2012) (Table 1). Although some functions of Enterococcus WTAs including evasion from the lectin pathways of the human complement system have recently been described (Geiss-Liebisch et al, 2012) it still has to be elucidated how and why enterococci glycosylate their WTA. Similar to enterococci streptococci such as Streptococcus pneumoniae synthesize very complex polymers with identical repeating units in WTA and LTA, which are glycosylated with GalNAc (Denapaite et al, 2012) (Table 1) although recent studies on S. pneumoniae LTA suggest no any glycosylation, possibly its WTA was not glycosylated either (Gisch et al, 2013).…”

Section: Role Of Wta Glycosylation In Other Gram-positive Bacteriamentioning

confidence: 99%

“…One of the most important S. aureus nasal colonization factors is the cell wallbound wall teichoic acid (WTA) (Weidenmaier et al, 2004), a cell surface polymer produced by most Gram-positive bacteria including major human pathogens such as Streptococcus pneumoniae, Listeria monocytogenes or Enterococcus faecalis (Denapaite et al, 2012;Fiedler, 1988;Geiss-Liebisch et al, 2012). Interestingly, WTA structures are highly diverse among Gram-positive bacteria and are often strain or species-specific (Neuhaus and Baddiley, 2003;Weidenmaier and Peschel, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Pathways and roles of wall teichoic acid glycosylation in Staphylococcus aureus

Winstel

Xia

Peschel

2014

International Journal of Medical Microbiology

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a b s t r a c tThe thick peptidoglycan layers of Gram-positive bacteria are connected to polyanionic glycopolymers called wall teichoic acids (WTA). Pathogens such as Staphylococcus aureus, Listeria monocytogenes, or Enterococcus faecalis produce WTA with diverse, usually strain-specific structure. Extensive studies on S. aureus WTA mutants revealed important functions of WTA in cell division, growth, morphogenesis, resistance to antimicrobials, and interaction with host or phages. While most of the S. aureus WTA-biosynthetic genes have been identified it remained unclear for long how and why S. aureus glycosylates WTA with ␣-or ␤-linked N-acetylglucosamine (GlcNAc). Only recently the discovery of two WTA glycosyltransferases, TarM and TarS, yielded fundamental insights into the roles of S. aureus WTA glycosylation. Mutants lacking WTA GlcNAc are resistant towards most of the S. aureus phages and, surprisingly, TarS-mediated WTA ␤-O-GlcNAc modification is essential for ␤-lactam resistance in methicillin-resistant S. aureus. Notably, S. aureus WTA GlcNAc residues are major antigens and activate the complement system contributing to opsonophagocytosis. WTA glycosylation with a variety of sugars and corresponding glycosyltransferases were also identified in other Gram-positive bacteria, which paves the way for detailed investigations on the diverse roles of WTA modification with sugar residues.

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“…The assembly pathways and functions of WTA and LTA of enterococci have not yet been thoroughly studied and elucidated. However, inactivation of the tagB gene in E. faecalis V583 leads to abrogation of the synthesis of two WTAs, which was associated with an increased susceptibility to complement-mediated killing by neutrophils [100]. In other Gram-positive microbes, WTAs entail many different functions including attachment to host tissues, cell division or abscess formation, and may be a target for opsonic antibodies [89].…”

Section: µMmentioning

confidence: 99%

The Cell Wall Architecture of Enterococcus Faecium : From Resistance to Pathogenesis

2013

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The cell wall of Gram-positive bacteria functions as a surface organelle that continuously interacts with its environment through a plethora of cell wall-associated molecules. Enterococcus faecium is a normal inhabitant of the GI tract of mammals, but has recently become an important etiological agent of hospital-acquired infections in debilitated patients. Insights into the assembly and function of enterococcal cell wall components and their interactions with the host during colonization and infection are essential to explain the worldwide emergence of E. faecium as an important multiantibiotic-resistant nosocomial pathogen. Understanding the biochemistry of cell wall biogenesis and principles of antibiotic resistance at the molecular level may open up new frontiers in research on enterococci, particularly for the development of novel antimicrobial strategies. In this article, we outline the current knowledge on the most important antimicrobial resistance mechanisms that involve peptidoglycan synthesis and the role of cell wall constituents, including lipoteichoic acid, wall teichoic acid, capsular polysaccharides, LPxTG cell wall-anchored surface proteins, WxL-type surface proteins and pili, in the pathogenesis of E. faecium.

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Secondary Cell Wall Polymers of Enterococcus faecalis Are Critical for Resistance to Complement Activation via Mannose-binding Lectin

Cited by 50 publications

References 51 publications

Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci

Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci

Pathways and roles of wall teichoic acid glycosylation in Staphylococcus aureus

The Cell Wall Architecture of Enterococcus Faecium : From Resistance to Pathogenesis

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