Linezolid in the Focus of Antimicrobial Resistance of Enterococcus Species: A Global Overview of Genomic Studies

Abstract

Linezolid (LNZ) is a synthetic oxazolidinone antibiotic that inhibits bacterial protein synthesis through binding to ribosomal RNA, also preventing the assembly of the initiation complex during translation. It is one of the last-line therapeutic options for serious infections caused by problematic Gram-positive pathogens, including vancomycin-resistant and multidrug-resistant Enterococcus species. Data from recent large-scale studies show a 2.5-fold increase in the prevalence of clinical LNZ-resistant enterococci (LRE) over the past decade with a global detection rate of 1.1% for LNZ-resistant E. faecium (LREfm) and 2.2% for LNZ-resistant E. faecalis (LREfs). Most reported cases have originated from China, followed by South Korea and the United States. LREfm typically belongs to the high-risk clonal complex 17, whereas LREfs demonstrates a heterogeneous population structure. Mutations in the 23S rRNA and ribosomal proteins, as well as acquired resistance genes such as cfr, optrA, and poxtA are involved in the development of LNZ resistance among enterococci. Whole-genome sequencing (WGS) has been recognized as a gold standard for identifying the underlying molecular mechanisms. It exposes that numerous LRE isolates possess multiple LNZ resistance determinants and mutations, further complicating the treatment strategies. The present review article summarizes all known mutational and non-mutational LNZ resistance mechanisms and presents a global overview of WGS-based studies with emphasis on resistome analysis of clinical LREfs and LREfm isolates published in the literature during the period 2014-2025.

Keywords: Enterococcus faecalis; Enterococcus faecium; G2576T mutation; cfr; linezolid; linezolid resistance mechanisms; optrA; poxtA; whole-genome sequencing.

Figure 1

Linezolid resistance-associated mutations in enterococci affecting the peptidyl transferase loop of domain V in 23S rRNA. Base positions are referenced according to the Escherichia coli numbering. The nucleotides that contact directly with the linezolid are denoted by an asterisk. Mutations conferring resistance to linezolid are color-coded based on their significance: red for common variants with a well-established role, and blue for recently identified variants associated with advancements in sequencing technologies. Mutation positions are taken from Turner et al. [56].

Figure 2

Geographical distribution of studies reporting sequenced genomes of linezolid-resistant E. faecium and/or E. faecalis strains harboring 23S rRNA mutations and/or mutations in genes encoding ribosomal proteins L3, L4, and L22.

Figure 3

Geographical distribution of studies reporting sequenced genomes of linezolid-resistant E. faecium and/or E. faecalis strains harboring cfr, optrA or poxtA genes.