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Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.

ABSTRACT: Linezolid, which targets the ribosome, is a new synthetic antibiotic that is used for treatment of infections caused by Gram-positive pathogens. Clinical resistance to linezolid, so far, has been developing only slowly and has involved exclusively target site mutations. We have discovered that linezolid resistance in a methicillin-resistant Staphylococcus aureus hospital strain from Colombia is determined by the presence of the cfr gene whose product, Cfr methyltransferase, modifies adenosine at position 2503 in 23S rRNA in the large ribosomal subunit. The molecular model of the linezolid-ribosome complex reveals localization of A2503 within the drug binding site. The natural function of cfr likely involves protection against natural antibiotics whose site of action overlaps that of linezolid. In the chromosome of the clinical strain, cfr is linked to ermB, a gene responsible for dimethylation of A2058 in 23S rRNA. Coexpression of these two genes confers resistance to all the clinically relevant antibiotics that target the large ribosomal subunit. The association of the ermB/cfr operon with transposon and plasmid genetic elements indicates its possible mobile nature. This is the first example of clinical resistance to the synthetic drug linezolid which involves a natural resistance gene with the capability of disseminating among Gram-positive pathogenic strains.

SUBMITTER: Toh SM

PROVIDER: S-EPMC2711439 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.

Toh Seok-Ming SM Xiong Liqun L Arias Cesar A CA Villegas Maria V MV Lolans Karen K Quinn John J Mankin Alexander S AS

Molecular microbiology 20070601 6

Linezolid, which targets the ribosome, is a new synthetic antibiotic that is used for treatment of infections caused by Gram-positive pathogens. Clinical resistance to linezolid, so far, has been developing only slowly and has involved exclusively target site mutations. We have discovered that linezolid resistance in a methicillin-resistant Staphylococcus aureus hospital strain from Colombia is determined by the presence of the cfr gene whose product, Cfr methyltransferase, modifies adenosine at ...[more]

PMID: 17555436

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Project description:BACKGROUND:We previously reported the case of a 64-year-old man with mediastinitis caused by Staphylococcus aureus in which the infecting bacterium acquired linezolid resistance after only 14 days treatment with linezolid. We therefore investigated relevant clinical isolates for possible mechanisms of this rapid acquisition of linezolid resistance. METHODS:Using clinical S. aureus isolates, we assessed the in vitro mutation rate and performed stepwise selection for linezolid resistance. To investigate homologous recombination, sequences were determined for each of the 23S ribosomal RNA (23S rRNA) loci; analyzed sequences spanned the entirety of each 23S rRNA gene, including domain V, as well as the 16S-23S intergenic spacer regions. We additionally performed next-generation sequencing on clinical strains to identify single-nucleotide polymorphisms compared to the N315 genome. RESULTS:Strains isolated from the patient prior to linezolid exposure (M5-M7) showed higher-level linezolid resistance than N315, and the pre-exposure strain (M2) exhibited more rapid acquisition of linezolid resistance than did N315. However, the mutation rates of these and contemporaneous clinical isolates were similar to those of N315, and the isolates did not exhibit any mutations in hypermutation-related genes. Sequences of the 23S rRNA genes and 16S-23S intergenic spacer regions were identical among the pre- and post-exposure clinical strains. Notably, all of the pre-exposure isolates harbored a recQ missense mutation (Glu69Asp) with respect to N315; such a lesion may have affected short sequence recombination (facilitating, for example, recombination among rrn loci). We hypothesize that this mechanism contributed to rapid acquisition of linezolid resistance. CONCLUSIONS:Hypermutation and homologous recombination of the ribosomal RNA genes, including 23S rRNA genes, appear not to have been sources of the accelerated acquisition of linezolid resistance observed in our clinical case. Increased frequency of short sequence recombination may have resulted from a recQ variant in the infecting organism.

Project description:Nursing home residents are frequently colonized with various strains of methicillin-resistant Staphylococcus aureus (MRSA) but the intra-facility dynamics of strain-specific MRSA remains poorly understood. We aimed at identifying and quantifying the associations between acquisition and carriage of MRSA strains and their potential risk factors in community nursing homes using mathematical modeling.The data was collected during a longitudinal MRSA surveillance study in six nursing homes in South Central Wisconsin. MRSA cultures were obtained from subjects every 3 months for up to one year. MRSA isolates were subsequently strain-typed by pulsed-field gel electrophoresis (PFGE), and their genetic similarity was established based on the Dice coefficients. Bayesian network analysis, logistic regression and elastic net were used to quantify the associations between acquisition and carriage of MRSA strains discriminated at 80% and 95% strain similarity thresholds and potentially modifiable resident characteristics including previous antibiotic exposure, comorbidity, medical devices, chronic wounds, functional and cognitive status and recent hospitalizations.Absence of severe cognitive impairment as well as presence of a wound, device and severe comorbidity was associated with elevated probability of USA100 carriage although there was a variation based on the combination of those risk factors. Residents with severe comorbidity and cognitive status and presence of device and wound were identified as certain carriers of USA100 in our sample. Residents with a chronic wound were more likely to carry USA100 MRSA (OR?=?2.77, 95% CI?=?1.37-5.87). Functional status was identified as an important determinant of carriage of USA100 and USA300 strains. Comorbidity and cognitive status were the two factors associated with carriage of all clonal groups in the study (USA100, USA300 and USA1200).The combination of Bayesian network analysis, logistic regression and elastic net can be used to identify associations between acquisition and carriage of MRSA strains and their potential risk factors in the face of scarce data. The revealed associations may be used to generate hypothesis for further study of determinants of acquisition and carriage of selected MRSA subtypes and to better inform infection control efforts in community nursing homes.

Dataset Information

Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.

Publications

Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.

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