Oxazolidinones: mechanisms of resistance and mobile genetic elements involved

Abstract

The oxazolidinones (linezolid and tedizolid) are last-resort antimicrobial agents used for the treatment of severe infections in humans caused by MDR Gram-positive bacteria. They bind to the peptidyl transferase centre of the bacterial ribosome inhibiting protein synthesis. Even if the majority of Gram-positive bacteria remain susceptible to oxazolidinones, resistant isolates have been reported worldwide. Apart from mutations, affecting mostly the 23S rDNA genes and selected ribosomal proteins, acquisition of resistance genes (cfr and cfr-like, optrA and poxtA), often associated with mobile genetic elements [such as non-conjugative and conjugative plasmids, transposons, integrative and conjugative elements (ICEs), prophages and translocatable units], plays a critical role in oxazolidinone resistance. In this review, we briefly summarize the current knowledge on oxazolidinone resistance mechanisms and provide an overview on the diversity of the mobile genetic elements carrying oxazolidinone resistance genes in Gram-positive and Gram-negative bacteria.

Detection of an Enterococcus faecium Carrying a Double Copy of the PoxtA Gene from Freshwater River, Italy

“…Recently, the occurrence of two poxtA copies was reported in the genomes of two isolates of swine origin, Lactobacillus salivarius BNS11 and E. hirae HDC14-2. Nevertheless, the genes were not on the same genetic element but instead were on the pBNS11-37 plasmid and chromosome as well as on two different plasmids (pHDC14-2.27K and pHDC14-2.133K), respectively [ 9 , 38 ]. The significance of the two detected poxtA copies is unclear; the occurrence of a second gene does not appear to affect the susceptibility of E. faecium M1 to oxazolidinones since the isolate was intermediate to linezolid and susceptible to tedizolid.…”

“…Resistance to linezolid can arise via mutations in the 23S rRNA and ribosomal proteins L3 and L4, but also through the acquisition of transferable resistance genes: cfr and its variants, poxtA and poxtA2 as well as optrA [ 9 ]. Cfr and Cfr-like methylases confer resistance to five classes of antimicrobial agents, including phenicols, lincosamides, oxazolidinones, pleuromutilines, and streptogramin A (PhLOPS A phenotype) via the post-transcriptional methylation of the 23S rRNA [ 10 ].…”

“…Although oxazolidinones have only been approved for clinical use, an increasing number of linezolid-resistant enterococci has been detected in animal [ 9 , 12 , 13 , 14 ] and environmental settings [ 15 , 16 , 17 ].…”

Spreading of cfr -Carrying Plasmids among Staphylococci from Humans and Animals

“…Both plasmid-borne and chromosome-borne cfr genes were detected in Staphylococcus spp. of various origins ( 7 – 9 ). Based on the staphylococcal cfr -containing sequences in the NCBI GenBank database, the cfr gene was present on plasmids in the majority of staphylococci of both human (27/32 isolates) and animal (30/38 isolates) origin (see Table S5 in the supplemental material).…”

“…The gene cfr encodes an RNA methyltransferase that mediates resistance against phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A antimicrobial agents ( 4 , 5 ). During the past 2 decades, this gene has been disseminated globally in bacteria of human and animal origin ( 6 – 9 ). Mobile genetic elements play a crucial role in the dissemination of cfr , among which plasmids are the preferred vectors ( 7 , 8 ).…”