Impact of antibiotic treatment and host innate immune pressure on enterococcal adaptation in the human bloodstream

Abstract

Multidrug-resistant enterococcal strains emerged in the early 1980s and are now among the leading causes of drug-resistant bacterial infection worldwide. We used functional genomics to study an early bacterial outbreak in patients in a Wisconsin hospital between 1984 and 1988 that was caused by multidrug-resistant Enterococcus faecalis. The goal was to determine how a clonal lineage of E. faecalis became adapted to growth and survival in the human bloodstream. Genome sequence analysis revealed a progression of increasingly fixed mutations and repeated independent occurrences of mutations in a relatively small set of genes. Repeated independent mutations suggested selection within the host during the course of infection in response to pressures such as host immunity and antibiotic treatment. We observed repeated independent mutations in a small number of loci, including a little studied polysaccharide utilization pathway and the cydABDC locus. Functional studies showed that mutating these loci rendered E. faecalis better able to withstand antibiotic pressure and innate immune defenses in the human bloodstream. We also observed a shift in mutation pattern that corresponded to the introduction of carbapenem antibiotics in 1987. This work identifies pathways that allow enterococci to survive the transition from the human gut into the bloodstream, enabling them to cause severe bacteremia associated with high mortality.

Enterococcus faecalis CRISPR-Cas Is a Robust Barrier to Conjugative Antibiotic Resistance Dissemination in the Murine Intestine

“…faecalis strains causing HAIs possess unique characteristics relative to strains that normally colonize the human intestine. HAI strains typically have larger genomes resulting from rampant plasmid, phage, and other MGE acquisition (9, 10). Multidrug-resistant (MDR) E.…”

Microbiota Research: From History to Advances

“…Inhibition of these enzymes might alleviate adverse reactions in patients treated with irinotecan-dependent drugs. This study provided a new solution to the problem of adverse drug reactions in patients [20].…”

“…On the other hand, the disorder of intestinal flora is closely related to the occurrence of various diseases. In addition to being closely related to the digestive system and metabolism [4][5][6][7] could also affect nerve function [8][9][10][11][12], aging [13][14][15], and even the immune system [16][17][18][19][20][21]. According to the summer meeting of the nutrition society held in University of Glasgow in 2000, intestine is one of the largest immune organ [22].…”

Enterococcus faecalisCRISPR-Cas is a robust barrier to conjugative antibiotic resistance dissemination in the murine intestine

“…E. faecalis strains causing HAIs possess unique characteristics relative to strains that normally colonize the human intestine. HAI strains typically have larger genomes resulting from rampant plasmid, phage, and other MGE acquisition (8, 9). Multidrug-resistant (MDR) E. faecalis generally lack CRISPR-Cas systems, and there is a correlation between the absence of CRISPR-Cas and the presence of horizontally acquired antibiotic resistance in E. faecalis clinical isolates (10).…”