Distribution of mec regulator genes in methicillin-resistant Staphylococcus clinical strains

Suzuki, Emiko; Kuwahara‐Arai, Kyoko; Richardson, Judith; Hiramatsu, Kazumasa

doi:10.1128/aac.37.6.1219

Cited by 139 publications

(128 citation statements)

References 33 publications

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“…The ccr and mec genes that are the basis of SCCmec typing are thought to have first been introduced into coagulase-negative staphylococci (4,26,27) from an unknown source, where deletion of the mec regulatory genes occurred, and then into S. aureus. It is unclear which staphylococcal species donated the four SCCmec types found among MRSAs, but the presence of four types suggests multiple introductions into S. aureus, and their presence in the same ST indicates that horizontal transfer of mec genes is relatively frequent within S. aureus.…”

Section: Discussionmentioning

confidence: 99%

The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA)

Enright

Robinson²,

Randle³

et al. 2002

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

1,432

1,179

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Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired infections that are becoming increasingly difficult to combat because of emerging resistance to all current antibiotic classes. The evolutionary origins of MRSA are poorly understood, no rational nomenclature exists, and there is no consensus on the number of major MRSA clones or the relatedness of clones described from different countries. We resolve all of these issues and provide a more thorough and precise analysis of the evolution of MRSA clones than has previously been possible. Using multilocus sequence typing and an algorithm, BURST, we analyzed an international collection of 912 MRSA and methicillinsusceptible S. aureus (MSSA) isolates. We identified 11 major MRSA clones within five groups of related genotypes. The putative ancestral genotype of each group and the most parsimonious patterns of descent of isolates from each ancestor were inferred by using BURST, which, together with analysis of the methicillin resistance genes, established the likely evolutionary origins of each major MRSA clone, the genotype of the original MRSA clone and its MSSA progenitor, and the extent of acquisition and horizontal movement of the methicillin resistance genes. Major MRSA clones have arisen repeatedly from successful epidemic MSSA strains, and isolates with decreased susceptibility to vancomycin, the antibiotic of last resort, are arising from some of these major MRSA clones, highlighting a depressing progression of increasing drug resistance within a small number of ecologically successful S. aureus genotypes.

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Section: Discussionmentioning

confidence: 99%

The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA)

Enright

Robinson²,

Randle³

et al. 2002

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

1,432

1,179

View full text Add to dashboard Cite

show abstract

“…Indeed, due to the potency of the MecI repressor, many methicillin-resistant S. aureus strains have MecI deletions that inactivate repression (16), incurring either constitutive expression of PBP2a or inducible expression regulated by BlaR1/BlaI. The recent observation that the absence of the bla or mec regulatory genes selects against PBP2a expression suggests a role for these genes in stabilizing dissemination of mecA to new host strains (17).…”

mentioning

confidence: 99%

Crystal Structures of the Apo and Penicillin-acylated Forms of the BlaR1 β-Lactam Sensor of Staphylococcus aureus

Wilke

Hills

Zhang

et al. 2004

Journal of Biological Chemistry

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Staphylococcus aureus is among the most prevalent and antibiotic-resistant of pathogenic bacteria. The resistance of S. aureus to prototypal ␤-lactam antibiotics is conferred by two mechanisms: (i) secretion of hydrolytic ␤-lactamase enzymes and (ii) production of ␤-lactam-insensitive penicillin-binding proteins (PBP2a). Despite their distinct modes of resistance, expression of these proteins is controlled by similar regulation systems, including a repressor (BlaI/MecI) and a multidomain transmembrane receptor (BlaR1/MecR1). Resistance is triggered in response to a covalent binding event between a ␤-lactam antibiotic and the extracellular sensor domain of BlaR1/MecR1 by transduction of the binding signal to an intracellular protease domain capable of repressor inactivation. This study describes the first crystal structures of the sensor domain of BlaR1 (BlaR S ) from S. aureus in both the apo and penicillin-acylated forms. The structures show that the sensor domain resembles the ␤-lactam-hydrolyzing class D ␤-lactamases, but is rendered a penicillin-binding protein due to the formation of a very stable acyl-enzyme. Surprisingly, conformational changes upon penicillin binding were not observed in our structures, supporting the hypothesis that transduction of the antibiotic-binding signal into the cytosol is mediated by additional intramolecular interactions of the sensor domain with an adjacent extracellular loop in BlaR1.The evolution and dissemination of antibiotic resistance in pathogenic bacteria are a growing concern. Many of the antimicrobial "wonder drugs" society has come to rely on for the treatment of bacterial infections have been neutralized by new strains equipped with a variety of molecular countermeasures. Methicillin-resistant Staphylococcus aureus is a prominent example of this (1-3). Although ␤-lactam antibiotics such as penicillin have long been the drugs of choice for infections of S. aureus, current therapies for methicillin-resistant S. aureus infections now depend on distinct antibiotic classes such as glycopeptides to counter the increased resistance to penicillin and its derivatives. The recent emergence of glycopeptide-resistant strains of S. aureus (4, 5) underscores the need not only for the development of novel therapeutics, but for better understanding of the molecular mechanisms involved in antibiotic resistance.␤-Lactam antibiotics kill bacteria by inhibiting the cell wall transpeptidases (also known as penicillin-binding proteins (PBPs) 1 ) that are responsible for the essential cross-linking of peptidoglycan during synthesis of the rigid bacterial cell wall. Resistance to ␤-lactam antibiotics in S. aureus can be conferred by two mechanisms. In one case, ␤-lactamase enzymes are secreted from the bacterium to hydrolytically inactivate ␤-lactam antibiotics. Resistance of this form is encoded by the blaZ gene and is carried by Ͼ95% of S. aureus isolates (3). The second resistance mechanism is expression of PBP2a, a cell wall transpeptidase with broad-spectrum insensitivity to ␤-lacta...

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“…Strains with intact mecImecR1 regulon are phenotypically methicillin sensitive, since mecA is effectively repressed by MecI (260). Constitutive expression of methicillin resistance requires alterations in regulatory genes and absence of beta-lactamase regulatory genes (blaI and blaR1), which are also able to repress mecA (98).…”

Section: Methicillin Resistancementioning

confidence: 99%

“…Constitutive expression of methicillin resistance requires alterations in regulatory genes and absence of beta-lactamase regulatory genes (blaI and blaR1), which are also able to repress mecA (98). Clinical MRSA isolates show deletions in mecI and some mecR1 regions, or mutations in mecI or in the promoter region of mecA (133,260). Some strains express methicillin resistance heterogeneously; only a small subset of the population (10 -3 -10 -7 ) is resistant to high methicillin concentrations.…”

Section: Methicillin Resistancementioning

confidence: 99%

“…The MLST was used to delineate the clonality and evolution of the most common Finnish MRSA strains identified during 1997-1999 (publication IV) 4.6.6 mec regulatory region PCR Using primers and a PCR protocol described earlier (260), three different fragments within the mec regulatory region were separately amplified. The fragments were: 1) almost the entire mecI gene, 2) the penicillin binding domaine of the mecR1 gene, and 3) the membrane spanning domaine of the mecR1 gene.…”

Section: Multilocus Sequence Typingmentioning

confidence: 99%

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