Development of homogeneous expression of resistance in methicillin-resistant Staphylococcus aureus clinical strains is functionally associated with a β-lactam-mediated SOS response

Cuirolo, Arabela; Plata, Konrad; Rosato, Adriana E.

doi:10.1093/jac/dkp164

Cited by 34 publications

(92 citation statements)

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“…Nevertheless, Sigma B contributed to methicillin resistance but not heteroresistance in Staphylococcus epidermidis; inactivation of the anti-sigma factor RsbW switched heteroresistance to homogeneous high-level resistance (128). Heteroresistance to homogeneous high-resistance selection (HeR-HoR selection) by oxacillin was associated with an increased mutation rate and expression of mecA and the SOS response lexA/recA gene regulators (129). Increased expression of the agr (accessory gene regulator) system during HeR-HoR selection was required to tightly modulate SOS-mediated mutation rates, which then led to full expression of homogeneous oxacillin resistance in very heterogeneous clinical MRSA strains (130).…”

Section: Heteroresistance To ␤-Lactamsmentioning

confidence: 99%

Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity

2015

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SUMMARY “Heteroresistance” describes a phenomenon where subpopulations of seemingly isogenic bacteria exhibit a range of susceptibilities to a particular antibiotic. Unfortunately, a lack of standard methods to determine heteroresistance has led to inappropriate use of this term. Heteroresistance has been recognized since at least 1947 and occurs in Gram-positive and Gram-negative bacteria. Its clinical relevance may be considerable, since more resistant subpopulations may be selected during antimicrobial therapy. However, the use of nonstandard methods to define heteroresistance, which are costly and involve considerable labor and resources, precludes evaluating the clinical magnitude and severity of this phenomenon. We review the available literature on antibiotic heteroresistance and propose recommendations for definitions and determination criteria for heteroresistant bacteria. This will help in assessing the global clinical impact of heteroresistance and developing uniform guidelines for improved therapeutic outcomes.

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Section: Heteroresistance To ␤-Lactamsmentioning

confidence: 99%

Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity

2015

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“…RNA extractions for real-time reverse transcription-PCR (RT-PCR) and Northern blot analyses were performed as previously described (12,19,44). Total RNA was extracted using an RNeasy isolation kit (Qiagen); all RNA samples were analyzed by A 260 /A 280 spectrophotometry and gel electrophoresis to assess concentration and integrity and cleaned of potential DNA contamination by treating them with DNase as per manufacturer recommendations (Ambion, Inc., Austin, TX).…”

Section: Materials and Mediamentioning

confidence: 99%

“…Methicillin resistance in S. aureus is mediated by the acquisition of a penicillin-binding protein (PBP), PBP 2a, which has decreased affinity for ␤-lactam antibiotics but can continue to cross-link the cell wall once the native PBPs (i.e., PBPs 1 to 4) have been inactivated (23). A distinctive feature for most methicillin-resistant S. aureus (MRSA) strains is the heterogeneous expression of resistance, characterized by a small proportion (Յ0.1%) of the population expressing a high level of homogeneous resistance while most of the other isolates in the population express resistance to 10 g/ml (12,15,43). Daptomycin (DAP) is a cyclic anionic lipopeptide antibiotic that is produced by Streptomyces roseosporus (3) and is approved for treatment of skin and skin structure infections as well as treatment of bacteremia and right-side endocarditis caused by MRSA (1).…”

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confidence: 99%

VraSR Two-Component Regulatory System Contributes to mprF -Mediated Decreased Susceptibility to Daptomycin in In Vivo -Selected Clinical Strains of Methicillin-Resistant Staphylococcus aureus

Mehta

Cuirolo

Plata

et al. 2012

Antimicrob Agents Chemother

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113

118

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Daptomycin (DAP) is a new class of cyclic lipopeptide antibiotic highly active against methicillin-resistant Staphylococcus aureus (MRSA) infections. Proposed mechanisms involve disruption of the functional integrity of the bacterial membrane in a Cadependent manner. In the present work, we investigated the molecular basis of DAP resistance in a group of isogenic MRSA clinical strains obtained from patients with S. aureus infections after treatment with DAP. Different point mutations were found in the mprF gene in DAP-resistant (DR) strains. Investigation of the mprF L826F mutation in DR strains was accomplished by inactivation and transcomplementation of either full-length wild-type or mutated mprF in DAP-susceptible (DS) strains, revealing that they were mechanistically linked to the DR phenotype. However, our data suggested that mprF was not the only factor determining the resistance to DAP. Differential gene expression analysis showed upregulation of the two-component regulatory system vraSR. Inactivation of vraSR resulted in increased DAP susceptibility, while complementation of vraSR mutant strains restored DAP resistance to levels comparable to those observed in the corresponding DR wild-type strain. Electron microscopy analysis showed a thicker cell wall in DR CB5012 than DS CB5011, an effect that was related to the impact of vraSR and mprF mutations in the cell wall. Moreover, overexpression of vraSR in DS strains resulted in both increased resistance to DAP and decreased resistance to oxacillin, similar to the phenotype observed in DR strains. These results support the suggestion that, in addition to mutations in mprF, vraSR contributes to DAP resistance in the present group of clinical strains. Staphylococcus aureus is the most common Gram-positive pathogen among skin and soft tissue infections (2). Methicillin resistance in S. aureus is mediated by the acquisition of a penicillin-binding protein (PBP), PBP 2a, which has decreased affinity for ␤-lactam antibiotics but can continue to cross-link the cell wall once the native PBPs (i.e., PBPs 1 to 4) have been inactivated (23). A distinctive feature for most methicillin-resistant S. aureus (MRSA) strains is the heterogeneous expression of resistance, characterized by a small proportion (Յ0.1%) of the population expressing a high level of homogeneous resistance while most of the other isolates in the population express resistance to 10 g/ml (12, 15, 43). Daptomycin (DAP) is a cyclic anionic lipopeptide antibiotic that is produced by Streptomyces roseosporus (3) and is approved for treatment of skin and skin structure infections as well as treatment of bacteremia and right-side endocarditis caused by MRSA (1). The mechanism of action involves disruption of cytoplasmic membrane function, resulting in depolarization and cell death due to disruption of critical metabolic functions, such as protein, DNA, and RNA synthesis (2).The incidence of DAP resistance in clinical isolates is very low, and resistant strains display small increases in MIC (2). The exact m...

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“…Microbiología sistencia de manera homogénea, haciéndose clínicamente relevantes 3,28 . La no detección de estas cepas puede obedecer al empleo de discos de FOX para predecir la resistencia a oxacilina; esta cefamicina ha sido recomendada para las pruebas de resistencia fenotípicas, debido a que es un mejor inductor de mecA que la OX 3,14,28 .…”

Section: Artículo Originalunclassified

“…La no detección de estas cepas puede obedecer al empleo de discos de FOX para predecir la resistencia a oxacilina; esta cefamicina ha sido recomendada para las pruebas de resistencia fenotípicas, debido a que es un mejor inductor de mecA que la OX 3,14,28 . Acorde con referencias internacionales, todos los aislados de SARM permanecen susceptibles a QDA, TEC, FUS, LZD, FOS, TGC y MUP 3,4,11,28,29 ; por lo que todavía constituyen fármacos importantes para la antibioticoterapia de las infecciones por SARM en la localidad.…”

Section: Artículo Originalunclassified

Susceptibilidad antimicrobiana y diseminación policlonal de cepas de Staphylococcus aureus

Castellano¹,

Perozo

Parra

et al. 2014

Rev. chil. infectol.

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Development of homogeneous expression of resistance in methicillin-resistant Staphylococcus aureus clinical strains is functionally associated with a β-lactam-mediated SOS response

Abstract: The present results support the notion that SOS response is mechanistically involved in generating mutations that, in addition to mecA induction, allow the selection of a highly oxacillin-resistant population.

Cited by 34 publications

References 31 publications

Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity

Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity

VraSR Two-Component Regulatory System Contributes to mprF -Mediated Decreased Susceptibility to Daptomycin in In Vivo -Selected Clinical Strains of Methicillin-Resistant Staphylococcus aureus

Susceptibilidad antimicrobiana y diseminación policlonal de cepas de Staphylococcus aureus

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