Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Abstract

Linezolid is an oxazolidinone antibiotic in clinical use for the treatment of serious infections of resistant Gram-positive bacteria. It inhibits protein synthesis by binding to the peptidyl transferase center on the ribosome. Almost all known resistance mechanisms involve small alterations to the linezolid binding site, so this review will therefore focus on the various changes that can adversely affect drug binding and confer resistance. High-resolution structures of linezolid bound to the 50S ribosomal subunit show that it binds in a deep cleft that is surrounded by 23S rRNA nucleotides. Mutation of 23S rRNA has for some time been established as a linezolid resistance mechanism. Although ribosomal proteins L3 and L4 are located further away from the bound drug, mutations in specific regions of these proteins are increasingly being associated with linezolid resistance. However, very little evidence has been presented to confirm this. Furthermore, recent findings on the Cfr methyltransferase underscore the modification of 23S rRNA as a highly effective and transferable form of linezolid resistance. On a positive note, detailed knowledge of the linezolid binding site has facilitated the design of a new generation of oxazolidinones that show improved properties against the known resistance mechanisms. LINEZOLID

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

“…The nucleotide A2572 has been previously implicated in PTC antibiotic resistance acquired by induced-fit alterations that, although not directly interacting with the bound drugs, reshape the binding pocket via networks of remote interactions, most of which occur through the flexible nucleotide U2504 (56). In another S. aureus linezolid-resistant strain, a deletion of F127-H146 occurs in the rplC gene, which encodes uL3 rProtein (12). In wild-type uL3, this loop is located within the area described above, in the vicinity of 23S rRNA H90 nucleotides G2576-G2580, which reside in the second shell around the linezolid-binding pocket.…”

“…Nevertheless, the epidemiology of S. aureus is increasing (11). Resistance mutations in S. aureus are also associated with ribosomal protein (rProtein) uL3, located in proximity to the PTC, as well as with uL4 and uL22 rProteins, whose segments are exposed in the exit tunnel (12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina

“…Entre estos mecanismos, el principal es el de las mutaciones en el dominio V del ARNr 23S, siendo la mutación G2576U la más frecuentemente reportada (52). Estas mutaciones pueden presentarse en una, algunas o todas las copias de los genes que codifican el ARNr bacteriano y se ha observado una correlación directa entre el número de copias mutadas y el nivel de resistencia al linezolid (53).…”

Staphylococcus haemolyticus – an emerging threat in the twilight of the antibiotics age

“…As a rule, in the case of infections caused by staphylococci resistant to glycopeptides, treatment should be based on linezolid -a synthetic chemotherapeutic of the oxazolidinones drug class (Perry & Jarvis, 2001). Linezolid blocks protein synthesis by binding to 23S rRNA and preventing the creation of the translation initiation complex (Livermore, 2003;Long & Vester, 2012;Quiles-Melero et al, 2013). Resistance to linezolid amongst CNS is currently negligible; however, the first cases of S. haemolyticus strains resistant to linezolid have been reported in India and in various countries in Europe (Gupta et al, 2012;Mazzariol et al, 2012;Mendes et al, 2014a, b, c;Rajan et al, 2014;Tarazona et al, 2007).…”