Enterococcus faecium: evolution, adaptation, pathogenesis and emerging therapeutics

Abstract

The opportunistic pathogen Enterococcus faecium colonizes humans and a wide range of animals, endures numerous stresses, resists antibiotic treatment and stubbornly persists in clinical environments. The widespread application of antibiotics in hospitals and agriculture has contributed to the emergence of vancomycin-resistant E. faecium, which causes many hospital-acquired infections. In this Review, we explore recent discoveries about the evolutionary history, the environmental adaptation and the colonization and dissemination mechanisms of E. faecium and vancomycin-resistant E. faecium. These studies provide critical insights necessary for developing novel preventive and therapeutic approaches against vancomycin-resistant E. faecium and also reveal the intricate interrelationships between the environment, the microorganism and the host, providing knowledge that is broadly relevant to how antibiotic-resistant pathogens emerge and endure.

Figure 1:. Vancomycin-resistant E. faecium transmission and evolution.

Arrows represent transfers of genomic information between different isolates. Animal isolates have close evolutionary relationships with clinical isolates^,,, and are potentially the original sources of clinical strains; however, recent studies suggest limited gene transfer between animal and clinical isolates.^,, Limited gene transfer was also identified between commensal and clinical isolates and between human and livestock isolates.^, Effects of clinical strains on the evolution of animal strains still remain unknown, as indicated by the question mark. A few studies reported the isolation of clade A1 strains from companion animals.^, Additionally, with the increasing amount of surveillance studies, clade A1 strains were also found in environmental settings other than the hospital, such as in wastewater and wild birds.^, The roles of these environmental isolates in the continuous evolution of VREfm remain to be identified; therefore, they are represented with question marks. MGEs, mobile genomic elements.

Figure 2:. Roles of plasmids in antimicrobial resistance spread in E. faecium.

a| E. faecium strains isolated from different hosts contain different plasmid types, which were determined by the types of replication initiator proteins (RIP). Clinical isolates having the highest plasmid number and longest cumulative plasmid length. b| Plasmid partitioning systems such as toxin–antitoxin systems ensure the stable inheritance of plasmids in daughter cells. Additionally, plasmids that contain genes essential for bacterial survival in the host will also most likely be retained by bacteria. c| Plasmids are vectors for the horizontal transfer of other mobile genomic elements as well as associated resistance genes. Horizontal transfer can happen through conjugation, and genes encoding this machinery have been found in VREfm plasmids. Bacterial restriction–modification systems cleave improperly modified DNAs entering the cell. Restriction–modification systems enriched in clade A1 may facilitate plasmid exchange among these strains.^,

Figure 3:. Adaptive strategies of vancomycin-resistant E. faecium that promote survival and resistance to antimicrobials.

a| VREfm can form persister cells and become viable but nonculturable (VBNC) under stress,^– and become unresponsive to antibiotic killing. b| Identified responders to environmental stress include the stress protein Gls24, stringent response alarmone guanosine tetraphosphate (ppGpp), and sensory transduction systems such as two component systems (2CS) and three component systems (3CS).^,,– These factors modulate VREfm cellular status and turn on pathways that facilitate survival under adversity. c| VREfm accumulates resistance genes over prolonged exposure to adverse conditions through both genomic mutation and horizontal gene transfer.

Figure 4:. Colonization and pathogenicity of E. faecium.

Major steps of E. faecium infection are shown. In general, depletion of microbiota (part a) removes competitive microorganisms, thereby dampening host innate immunity, including a decrease in mucin production. These conditions favor E. faecium colonization and domination (part b) in the gastrointestinal (GI) tract. Following outgrowth in the gastrointestinal tract , E. faecium cells translocate (part c) into deeper tissues either through the microfold (M) cells or direct penetration, and then disseminate (part d) into other body locations through the bloodstream,^, leading to the development of systemic diseases. Representative virulence-associated processes and factors include bile acids inducing changes in cellular morphology, causing them to form chains; host attachment mediated by factors including pilus, capsule, wall teichoic acid (WTA), lipoteichoic acid (LTA), Enterococcus polysaccharide antigen (EPA), and cell surface proteins;^,, secreted factors including extracellular matrix (ECM) binding proteins,^, pore-forming toxin, and TirEs containing an interleukin-binding domain; and processes with unknown mediating factors such as stimulation of host formyl-peptide receptor 2 to induce inflammation, resistance to the killing effects of Group IIA-secreted phospholipase A2, and the presence of clade A1-specific phosphotransferase systems (PTSs) which facilitates the stress response, and metabolism of host-associated materials.^,,,