The Role of ArlRS and VraSR in Regulating Ceftaroline Hypersusceptibility in Methicillin-Resistant Staphylococcus aureus

Villanueva, Maite; Roch, Mélanie; Lasa, Íñigo; Renzoni, Adriana; Kelley, William L.

doi:10.3390/antibiotics10070821

Cited by 7 publications

(3 citation statements)

References 29 publications

(40 reference statements)

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“…However, it is unexpected to observe such differences in PBP2a expression between strains harboring similar SCC mec elements and MecI/MecR BlaI/BlaR regulons. These observations suggest the involvement of other regulatory elements such as two-component systems or global regulators (46, 47).…”

Section: Discussionmentioning

confidence: 90%

Proteomic assay for rapid characterization ofStaphylococcus aureusantimicrobial resistance directly from blood cultures

Deforet,

Carrière,

Dufour

et al. 2023

Preprint

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An efficient management of bloodstream infections requires a fast identification of the pathogen and a determination of its antimicrobial resistance profile.Staphylococcus aureusis among the most common pathogen causing bloodstream infection. A prompt characterization of methicillin-resistantStaphylococcus aureus(MRSA) and their aminoglycoside resistance profile is therefore crucial to quickly adapt the treatment and improve clinical outcomes. Among analytical technologies, targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a promising tool to detect resistance mechanisms in clinical samples. Herein we present a rapid proteomic workflow to detect and quantify the most clinically relevant antimicrobial resistance effectors inS. aureus: PBP2a, PBP2c, APH(3’)-III, ANT(4’)-I, and AAC(6’)-APH(2’’), directly from positive blood cultures and in less than 70 minutes. This approach provided 99% sensitivity for PBP2a (n=98/99 strains) detection. Sensitivity was 100% for PBP2c (n=5/5), APH(3’)-III (n=16/16) and ANT(4’)-I (n=20/20), and 94% for AAC(6’)-APH(2’’) (n=16/17). Across the entire collection, 100% specificity was reported for each of the 5 resistance proteins. Additionally, relative quantification of ANT(4’)-I expression allowed to discriminate kanamycin-susceptible and -resistant strains, in strains all harboring theant(4’)-Iagene. The LC-MS/MS method presented herein demonstrates its ability to provide a reliable and in-depth profiling ofS. aureusresistance, directly from positive blood culture and in a short turnaround time, as required in clinical laboratories.

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Section: Discussionmentioning

confidence: 90%

Proteomic assay for rapid characterization ofStaphylococcus aureusantimicrobial resistance directly from blood cultures

Deforet,

Carrière,

Dufour

et al. 2023

Preprint

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“…As a TCST that is unique in staphylococci, ArlRS has been proven to have vital functions in regulating S. epidermidis and S. aureus biofilm production, modulating S. aureus virulence and affecting antibiotic resistance in MRSA strains [ 101 ]. These findings indicate that ArlRS is a promising target for screening inhibitors that may eradicate young/mature biofilms, retard virulence and break antimicrobial resistance.…”

Section: Discussionmentioning

confidence: 99%

The Staphylococcus aureus ArlS Kinase Inhibitor Tilmicosin Has Potent Anti-Biofilm Activity in Both Static and Flow Conditions

Wang,

Bai

et al. 2024

Microorganisms

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Staphylococcus aureus can form biofilms on biotic surfaces or implanted materials, leading to biofilm-associated diseases in humans and animals that are refractory to conventional antibiotic treatment. Recent studies indicate that the unique ArlRS regulatory system in S. aureus is a promising target for screening inhibitors that may eradicate formed biofilms, retard virulence and break antimicrobial resistance. In this study, by screening in the library of FDA-approved drugs, tilmicosin was found to inhibit ArlS histidine kinase activity (IC50 = 1.09 μM). By constructing a promoter-fluorescence reporter system, we found that tilmicosin at a concentration of 0.75 μM or 1.5 μM displayed strong inhibition on the expression of the ArlRS regulon genes spx and mgrA in the S. aureus USA300 strain. Microplate assay and confocal laser scanning microscopy showed that tilmicosin at a sub-minimal inhibitory concentration (MIC) had a potent inhibitory effect on biofilms formed by multiple S. aureus strains and a strong biofilm-forming strain of S. epidermidis. In addition, tilmicosin at three-fold of MIC disrupted USA300 mature biofilms and had a strong bactericidal effect on embedded bacteria. Furthermore, in a BioFlux flow biofilm assay, tilmicosin showed potent anti-biofilm activity and synergized with oxacillin against USA300.

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“…In S. aureus , the activity and/or expression of several autolysins is controlled by various TCSs ( 23 – 25 ). Furthermore, different TCSs of S. aureus have already been implicated in MDR through modification of the cell wall, efflux mechanisms, and inhibition of drug uptake ( 26 , 27 ): WalKR and VraSR play a role in the resistance to vancomycin ( 28 – 31 ), BraRS affects the susceptibility to bacitracin and nisin ( 32 ), GraRS affects the susceptibility to cationic antimicrobial peptides ( 33 ), ArlRS regulates resistance to ceftaroline ( 34 ), and HptSR is related with resistance to fosfomycin ( 35 ). The absence of any of these TCSs increases susceptibility to the corresponding antibiotic.…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system

Gómez-Arrebola,

Hernandez,

Culp

et al. 2023

Microbiol Spectr

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The overuse of antibiotics in humans and livestock has driven the emergence and spread of antimicrobial resistance and has therefore prompted research on the discovery of novel antibiotics. Complestatin (Cm) and corbomycin (Cb) are glycopeptide antibiotics with an unprecedented mechanism of action that is active even against methicillin-resistant and daptomycin-resistant Staphylococcus aureus . They bind to peptidoglycan and block the activity of peptidoglycan hydrolases required for remodeling the cell wall during growth. Bacterial signaling through two-component transduction systems (TCSs) has been associated with the development of S. aureus antimicrobial resistance. However, the role of TCSs in S. aureus susceptibility to Cm and Cb has not been previously addressed. In this study, we determined that, among all 16 S. aureus TCSs, VraSR is the only one controlling the susceptibility to Cm and Cb. Deletion of vraSR increased bacterial susceptibility to both antibiotics. Epistasis analysis with members of the vraSR regulon revealed that deletion of spdC, which encodes a membrane protein that scaffolds SagB for cleavage of peptidoglycan strands to achieve physiological length, in the vraSR mutant restored Cm and Cb susceptibility to wild-type levels. Moreover, deletion of either spdC or sagB in the wild-type strain increased resistance to both antibiotics. Further analyses revealed a significant rise in the relative amount of peptidoglycan and its total degree of cross-linkage in ΔspdC and ΔsagB mutants compared to the wild-type strain, suggesting that these changes in the cell wall provide resistance to the damaging effect of Cm and Cb. IMPORTANCE Although Staphylococcus aureus is a common colonizer of the skin and digestive tract of humans and many animals, it is also a versatile pathogen responsible for causing a wide variety and number of infections. Treatment of these infections requires the bacteria to be constantly exposed to antibiotic treatment, which facilitates the selection of antibiotic-resistant strains. The development of new antibiotics is, therefore, urgently needed. In this paper, we investigated the role of the sensory system of S. aureus in susceptibility to two new antibiotics: corbomycin and complestatin. The results shed light on the cell-wall synthesis processes that are affected by the presence of the antibiotic and the sensory system responsible for coordinating their activity.

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The Role of ArlRS and VraSR in Regulating Ceftaroline Hypersusceptibility in Methicillin-Resistant Staphylococcus aureus

Cited by 7 publications

References 29 publications

Proteomic assay for rapid characterization ofStaphylococcus aureusantimicrobial resistance directly from blood cultures

Proteomic assay for rapid characterization ofStaphylococcus aureusantimicrobial resistance directly from blood cultures

The Staphylococcus aureus ArlS Kinase Inhibitor Tilmicosin Has Potent Anti-Biofilm Activity in Both Static and Flow Conditions

Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system

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