VraSR and Virulence Trait Modulation during Daptomycin Resistance in Methicillin-Resistant
            <i>Staphylococcus aureus</i>
            Infection

Taglialegna, Agustina; Varela, Maria Celeste; Rosato, Roberto R.; Rosato, Adriana E.

doi:10.1128/msphere.00557-18

Cited by 26 publications

(23 citation statements)

References 62 publications

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“…The two-component signal transduction system is widely distributed in bacteria. The VraSR two-component system is an important regulatory system in Staphylococcus aureus, allowing bacteria to sense changes in the external environment and to adjust their response to maintain its homeostasis (47,48). The VraSR twocomponent system consists of a histidine kinase sensor protein (VraS) and an effector regulatory protein (VraR) (49,50).…”

Section: Luxs/ai-2 Qs System Contributes To Antibiotic Resistancementioning

confidence: 99%

Regulatory Mechanisms of the LuxS/AI-2 System and Bacterial Resistance

Wang

Liu

Grenier

et al. 2019

Antimicrob Agents Chemother

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The quorum-sensing (QS) system is an intercellular cell-cell communication mechanism that controls the expression of genes involved in a variety of cellular processes and that plays critical roles in the adaption and survival of bacteria in their environment. The LuxS/AI-2 QS system, which uses AI-2 (autoinducer-2) as a signal molecule, has been identified in both Gram-negative and Gram-positive bacteria. As one of the important global regulatory networks in bacteria, it responds to fluctuations in the numbers of bacteria and regulates the expression of a number of genes, thus affecting cell behavior. We summarize here the known relationships between the LuxS/AI-2 system and drug resistance, discuss the inhibition of LuxS/AI-2 system as an approach to prevent bacterial resistance, and present new strategies for the treatment of drug-resistant pathogens.

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Section: Luxs/ai-2 Qs System Contributes To Antibiotic Resistancementioning

confidence: 99%

Regulatory Mechanisms of the LuxS/AI-2 System and Bacterial Resistance

Wang

Liu

Grenier

et al. 2019

Antimicrob Agents Chemother

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“…A third mechanism is the involvement of global regulatory genes modulating cell-envelope stress and maintenance, affecting the expression of the cell-wall (CW) “stimulon” ( Utaida et al, 2003 ; Cafiso et al, 2012 ). Specifically, VraSR operon ( Muthaiyan et al, 2008 ; Mehta et al, 2012 ; Sabat et al, 2018 ; Taglialegna et al, 2019 ), orthologous to the Bacillus subtilis LiaSR ( Jordan et al, 2006 ), was involved and up-regulated by vancomycin and DAP exposure, and associated with CW biosynthesis via transcription of PBP2 (penicillin-binding protein 2), tag A (wall teichoic acids-synthesis), prs A (a-chaperone), and mur Z (UDP- N -acetylglucosamine-enolpyruvyl transferase) ( Kuroda et al, 2003 ; Mwangi et al, 2007 ). YycFG (also named WalKR), among the two-component regulatory systems (TCRSs), was implicated in the control of the peptidoglycan biosynthesis through the regulation of LytM and AtlA ( Dubrac and Msadek, 2004 ; Fukushima et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Genomic and Long-Term Transcriptomic Imprints Related to the Daptomycin Mechanism of Action Occurring in Daptomycin- and Methicillin-Resistant Staphylococcus aureus Under Daptomycin Exposure

et al. 2020

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Daptomycin (DAP) is one of the last-resort treatments for heterogeneous vancomycinintermediate Staphylococcus aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) infections. DAP resistance (DAP-R) is multifactorial and mainly related to cellenvelope modifications caused by single-nucleotide polymorphisms and/or modulation mechanisms of transcription emerging as result of a self-defense process in response to DAP exposure. Nevertheless, the role of these adaptations remains unclear. We aim to investigate the comparative genomics and late post-exponential growthphase transcriptomics of two DAP-resistant/DAP-susceptible (DAP R/S) methicillinresistant S. aureus (MRSA) clinical strain pairs to focalize the genomic and longterm transcriptomic fingerprinting and adaptations related to the DAP mechanism of action acquired in vivo under DAP pressure using Illumina whole-genome sequencing (WGS), RNA-seq, bioinformatics, and real-time qPCR validation. Comparative genomics revealed that membrane protein and transcriptional regulator coding genes emerged as shared functional coding-gene clusters harboring mutational events related to the DAP-R onset in a strain-dependent manner. Pairwise transcriptomic enrichment analysis highlighted common and strain pair-dependent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, whereas DAP R/S double-pair cross-filtering returned 53 differentially expressed genes (DEGs). A multifactorial long-term transcriptomic-network characterized DAP R MRSA includes alterations in (i) peptidoglycan biosynthesis, cell division, and cell-membrane (CM) organization genes, as well as a cidB/lytS autolysin genes; (ii) ldh2 involved in fermentative metabolism; (iii) CM-potential perturbation genes; and (iv) oxidative and heat/cold stress response-related genes. Moreover, a D-alanyl-D-alanine decrease in cell-wall muropeptide characterized DAP/glycopeptide

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“…As a salient feature of vancomycin-intermediate S. aureus (VISA), CW thickening was reported one of the contributing factors to VCM resistance in some DAP R strains. In fact, mutations in either walK , encoding the sensor protein kinase of a two-component regulatory system, or vraSR , involved in cell envelope homeostasis, both of which resulted in CW thickening, were related to the DAP/VCM cross-resistance 29 , 30 . However, phenotypic changes in CW thickness were not consistently observed in all DAP R strains 26 , 31 .…”

Section: Introductionmentioning

confidence: 99%

Association of mprF mutations with cross-resistance to daptomycin and vancomycin in methicillin-resistant Staphylococcus aureus (MRSA)

Thitiananpakorn

Aiba

Tan

et al. 2020

Sci Rep

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We first reported a phenomenon of cross-resistance to vancomycin (VCM) and daptomycin (DAP) in methicillin-resistant Staphylococcus aureus (MRSA) in 2006, but mechanisms underlying the cross-resistance remain incompletely understood. Here, we present a follow-up study aimed to investigate genetic determinants associated with the cross-resistance. Using 12 sets of paired DAP susceptible (DAPS) and DAP non-susceptible (DAPR) MRSA isolates from 12 patients who had DAP therapy, we (i) assessed susceptibility to DAP and VCM, (ii) compared whole-genome sequences, (iii) identified mutations associated with cross-resistance to DAP and VCM, and (iv) investigated the impact of altered gene expression and metabolic pathway relevant to the cross-resistance. We found that all 12 DAPR strains exhibiting cross-resistance to DAP and VCM carried mutations in mprF, while one DAPR strain with reduced susceptibility to only DAP carried a lacF mutation. On the other hand, among the 32 vancomycin-intermediate S. aureus (VISA) strains isolated from patients treated with VCM, five out of the 18 strains showing cross-resistance to DAP and VCM carried a mprF mutation, while 14 strains resistant to only VCM had no mprF mutation. Moreover, substitution of mprF in a DAPS strain with mutated mprF resulted in cross-resistance and vice versa. The elevated lysyl-phosphatidylglycerol (L-PG) production, increased positive bacterial surface charges and activated cell wall (CW) synthetic pathways were commonly found in both clinical isolates and laboratory-developed mutants that carry mprF mutations. We conclude that mprF mutation is responsible for the cross-resistance of MRSA to DAP and VCM, and treatment with DAP is more likely to select for mprF-mediated cross-resistance than is with VCM.

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VraSR and Virulence Trait Modulation during Daptomycin Resistance in Methicillin-Resistant Staphylococcus aureus Infection

Cited by 26 publications

References 62 publications

Regulatory Mechanisms of the LuxS/AI-2 System and Bacterial Resistance

Regulatory Mechanisms of the LuxS/AI-2 System and Bacterial Resistance

Genomic and Long-Term Transcriptomic Imprints Related to the Daptomycin Mechanism of Action Occurring in Daptomycin- and Methicillin-Resistant Staphylococcus aureus Under Daptomycin Exposure

Association of mprF mutations with cross-resistance to daptomycin and vancomycin in methicillin-resistant Staphylococcus aureus (MRSA)

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