Inactivation of the Indigenous Methyltransferase RlmN in Staphylococcus aureus Increases Linezolid Resistance

LaMarre, Jacqueline M.; Howden, Benjamin P; Mankin, Alexander S.

doi:10.1128/aac.00183-11

Cited by 48 publications

(50 citation statements)

References 27 publications

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“…It is concluded from one study that an RlmN-deletion strain is outcompeted by wild-type cells in the absence of antibiotic selection and that RlmN methylation leads to a 2-fold decrease in linezolid susceptibility in S. aureus (90). In a follow-up study, the authors concede that the earlier MIC data are inconclusive (44). Subsequent competition experiments show that cells with an inactivated rlmN gene outcompeted wild-type cells under linezolid selection (44).…”

Section: Does Linezolid Resistance Come With a Cost And How Is It Relmentioning

confidence: 93%

“…Inactivation of the spr0333 methyltransferase targeting G2445 in 23S rRNA results in decreased susceptibility to linezolid in S. pneumoniae (3,19). Likewise, mutations inactivating the methyltransferase RlmN, which methylates the C-2 position of A2503 of 23S rRNA, also lower linezolid susceptibility in S. aureus (23,44,88). The only known transferable form of linezolid resistance is conferred by the multiresistance gene cfr, which encodes an rRNA methyltransferase (39).…”

Section: Resistance Caused By Alterations In 23s Rrna Modificationmentioning

confidence: 99%

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

Long

Vester

2012

Antimicrob Agents Chemother

313

195

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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

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Section: Does Linezolid Resistance Come With a Cost And How Is It Relmentioning

confidence: 93%

Section: Resistance Caused By Alterations In 23s Rrna Modificationmentioning

confidence: 99%

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

Long

Vester

2012

Antimicrob Agents Chemother

313

195

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“…A2503 methylation of C8 by Cfr, which increases its size, interferes with PhLOPS A drug binding, thereby conferring resistance to these drugs. In addition, hindering the C2 position of A2503 indigenous methylation by inactivating the gene of the methyltransferase RlmN renders resistance to linezolid, because a lack of methyl substitution may change its orientation with respect to the drug (25,68) (Fig. 6 A and B).…”

Section: Resultsmentioning

confidence: 99%

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

Eyal

Matzov

Krupkin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

121

151

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The emergence of bacterial multidrug resistance to antibiotics threatens to cause regression to the preantibiotic era. Here we present the crystal structure of the large ribosomal subunit from Staphylococcus aureus, a versatile Gram-positive aggressive pathogen, and its complexes with the known antibiotics linezolid and telithromycin, as well as with a new, highly potent pleuromutilin derivative, BC-3205. These crystal structures shed light on specific structural motifs of the S. aureus ribosome and the binding modes of the aforementioned antibiotics. Moreover, by analyzing the ribosome structure and comparing it with those of nonpathogenic bacterial models, we identified some unique internal and peripheral structural motifs that may be potential candidates for improving known antibiotics and for use in the design of selective antibiotic drugs against S. aureus.

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“…Recent additions to the long list of its resistant mutants have been described in several review articles (84)(85)(86). The methicillin-resistant S. aureus (MRSA) strain is considered to be one of the most common and problematic bacteria associated with increasing antimicrobial resistance.…”

Section: Figurementioning

confidence: 99%

A Bright Future for Antibiotics?

Matzov

Bashan²,

Yonath³

2017

Annu. Rev. Biochem.

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Multidrug resistance is a global threat as the clinically available potent antibiotic drugs are becoming exceedingly scarce. For example, increasing drug resistance among gram-positive bacteria is responsible for approximately one-third of nosocomial infections. As ribosomes are a major target for these drugs, they may serve as suitable objects for novel development of next-generation antibiotics. Three-dimensional structures of ribosomal particles from Staphylococcus aureus obtained by X-ray crystallography have shed light on fine details of drug binding sites and have revealed unique structural motifs specific for this pathogenic strain, which may be used for the design of novel degradable pathogen-specific, and hence, environmentally friendly drugs.

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Inactivation of the Indigenous Methyltransferase RlmN in Staphylococcus aureus Increases Linezolid Resistance

Cited by 48 publications

References 27 publications

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

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

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

A Bright Future for Antibiotics?

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