Regulation of Resistance in Vancomycin-Resistant Enterococci: The VanRS Two-Component System

Guffey, Alexandra A.; Loll, Patrick J.

doi:10.3390/microorganisms9102026

Cited by 34 publications

(31 citation statements)

References 244 publications

(385 reference statements)

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“…We also tested how the absence of D‐Ala‐D‐Ala in peptidoglycan affects the ability of vancomycin to activate VanS and induce the vanG operon. The actual effector of VanS remains unknown despite extensive investigation in several bacterial species (Guffey & Loll, 2021; Kwun et al, 2013; Lockey et al, 2020; Upton et al, 2019). No information is available on the mechanism of activation of the VanS proteins associated with vanG operons.…”

Section: Resultsmentioning

confidence: 99%

“…The van operons are normally induced by vancomycin and, sometimes, other glycopeptide antibiotics that bind to the D‐Ala‐D‐Ala groups of peptidoglycan. Each van operon is regulated by an adjacent two‐component system, vanRS , which encodes VanR, a response regulator of the OmpR/PhoB family, and VanS, a histidine kinase that is responsible for sensing vancomycin (Depardieu & Courvalin, 2017; Guffey & Loll, 2021; Hong et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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VanG‐ and D‐Ala‐D‐Ser‐dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile

Belitsky

2022

Molecular Microbiology

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A Clostridioides difficile strain deficient in the ddl gene is unable to synthesize the dipeptide D‐Ala‐D‐Ala, an essential component of peptidoglycan and the target of vancomycin. We isolated spontaneous suppressors of a ∆ddl mutation that allowed cell growth in the absence of D‐Ala‐D‐Ala. The mutations caused constitutive or partly constitutive expression of the vancomycin‐inducible vanG operon responsible for the synthesis of D‐Ala‐D‐Ser, which can replace D‐Ala‐D‐Ala in peptidoglycan. The mutations mapped to the vanS or vanR genes, which regulate expression of the vanG operon. The constitutive level of vanG expression was about 10‐fold above that obtained by vancomycin induction. The incorporation of D‐Ala‐D‐Ser into peptidoglycan due to high expression of the vanG operon conferred only low‐level resistance to vancomycin, but VanG was found to synthesize D‐Ala‐D‐Ala in addition to D‐Ala‐D‐Ser. However, the same, low resistance to vancomycin was also observed in cells completely unable to synthesize D‐Ala‐D‐Ala and grown in the presence of D‐Ala‐D‐Ser. D‐Ala‐D‐Ala presence was required for efficient vancomycin induction of the vanG operon showing that vancomycin is not by itself able to activate VanS. D‐Ala‐D‐Ser, similar to D‐Ala‐D‐Ala, served as an anti‐activator of DdlR, the positive regulator of the ddl gene, thereby coupling vanG and ddl expression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

VanG‐ and D‐Ala‐D‐Ser‐dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile

Belitsky

2022

Molecular Microbiology

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“…The vanHAX operon is regulated at the transcriptional level by the two-component VanR/VanS regulatory system in response to vancomycin [88]. In this case, vancomycin activates the membrane sensory kinase VanS, which, in turn, phosphorylates the transcription regulator VanR that drives the expression of the vanHAX operon [88,144] (Figure 1A). The van gene cluster has been found in human pathogens such as Enterococcus faecalis, Enterococcus faecium, and Staphylococcus aureus [88].…”

Section: Alterations Of the Target That Disable The Binding Of Antibi...mentioning

confidence: 99%

Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria

Sionov

Steinberg

2022

Microorganisms

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Chronic and recurrent bacterial infections are frequently associated with the formation of biofilms on biotic or abiotic materials that are composed of mono- or multi-species cultures of bacteria/fungi embedded in an extracellular matrix produced by the microorganisms. Biofilm formation is, among others, regulated by quorum sensing (QS) which is an interbacterial communication system usually composed of two-component systems (TCSs) of secreted autoinducer compounds that activate signal transduction pathways through interaction with their respective receptors. Embedded in the biofilms, the bacteria are protected from environmental stress stimuli, and they often show reduced responses to antibiotics, making it difficult to eradicate the bacterial infection. Besides reduced penetration of antibiotics through the intricate structure of the biofilms, the sessile biofilm-embedded bacteria show reduced metabolic activity making them intrinsically less sensitive to antibiotics. Moreover, they frequently express elevated levels of efflux pumps that extrude antibiotics, thereby reducing their intracellular levels. Some efflux pumps are involved in the secretion of QS compounds and biofilm-related materials, besides being important for removing toxic substances from the bacteria. Some efflux pump inhibitors (EPIs) have been shown to both prevent biofilm formation and sensitize the bacteria to antibiotics, suggesting a relationship between these processes. Additionally, QS inhibitors or quenchers may affect antibiotic susceptibility. Thus, targeting elements that regulate QS and biofilm formation might be a promising approach to combat antibiotic-resistant biofilm-related bacterial infections.

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“…The gene vanH encodes dehydrogenase responsible for reduction of pyruvate to D-lactate, vanX encodes dipeptidase responsible for the hydrolysis of D-Ala-D-Ala, and vanA encodes a ligase for the synthesis of D-Ala-D-Lac. 7 S, a two-component system, regulates the expression of the vanHAX gene cluster. The presence of glycopeptide antibiotics causes autophosphorylation of membrane-associated VanS (a sensor kinase) followed by activation of a cytoplasmic response regulator and transcriptional activator, vanR protein, that is responsible for activation of the vanA operon.…”

Section: Introductionmentioning

confidence: 99%

“…Among 11 different operons identified in VRE, the most common vanA operon (vanHAX gene cluster) consists of three resistance genes, vanH, vanX, and vanA. The gene vanH encodes dehydrogenase responsible for reduction of pyruvate to d -lactate, vanX encodes dipeptidase responsible for the hydrolysis of d -Ala- d -Ala, and vanA encodes a ligase for the synthesis of d -Ala- d -Lac . vanR/S, a two-component system, regulates the expression of the vanHAX gene cluster.…”

Section: Introductionmentioning

confidence: 99%

Targeting Vancomycin-ResistantEnterococci(VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric Cholic Acid–Peptide Conjugates

et al. 2022

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Emergence of vancomycin resistance in Gram-positive bacteria and the prevalence of vancomycin-resistant Enterococci (VRE) infections are highly alarming as very limited antibiotic options are available against VRE infections. Here, we present the synthesis of cholic acid-derived dimeric amphiphiles where two cholic acid moieties are tethered through carboxyl terminals using different alkylene spacers. Our investigations revealed that dimer 5 possessing a propylene spacer and glycine-valine peptides tethered on hydroxyl groups is the most effective antimicrobial against VRE. Dimer 5 can permeabilize bacterial membranes, generate reactive oxygen species, and clear preformed biofilms. We further demonstrate that dimer 5 downregulates vancomycinmediated transcriptional activation of the vanHAX gene cluster and does not allow VSE to develop vancomycin resistance until 100 generations. Therefore, this study, for the first time, presents a bacterial membrane-targeting amphiphile that can mitigate VRE infections and inhibit the emergence of vancomycin resistance.

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Regulation of Resistance in Vancomycin-Resistant Enterococci: The VanRS Two-Component System

Cited by 34 publications

References 244 publications

VanG‐ and D‐Ala‐D‐Ser‐dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile

VanG‐ and D‐Ala‐D‐Ser‐dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile

Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria

Targeting Vancomycin-ResistantEnterococci(VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric Cholic Acid–Peptide Conjugates

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