Prevalence of amino acid changes in the yvqF, vraSR, graSR, and tcaRAB genes from vancomycin intermediate resistant Staphylococcus aureus

Yoo, Jae Il; Kim, Jung Wook; Kang, Gi Su; Kim, Hwa Su; Yoo, Jung Sik; Lee, Yeong Seon

doi:10.1007/s12275-013-3088-7

Cited by 27 publications

(22 citation statements)

References 22 publications

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“…Global comparison with the transcriptional responses to daptomycin and LL16 shows that brilacidin has certain similarities to both treatments, specifically in its ability to induce the GraSR, NsaSR, VraSR, and WalKR two-component systems (TCSs), with an enhanced upregulation of the cell wall stress regulons. These TCSs are induced by cell membrane-and cell wall-damaging agents and are also involved in resistance to these antibiotics (57)(58)(59), which is consistent with the hypothesized mechanism of action of these drugs. Interestingly, recent reports on the mechanism of a novel vancomycin-derivative lipoglycopeptidic drug, telavancin, show curious similarities and key differences in the induction of these TCSs.…”

Section: Discussionsupporting

confidence: 79%

Comparative Mechanistic Studies of Brilacidin, Daptomycin, and the Antimicrobial Peptide LL16

Mensa

Howell

Scott³

et al. 2014

Antimicrob Agents Chemother

161

155

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b Brilacidin (PMX30063) has shown potent bactericidal activity against drug-resistant and -susceptible strains of multiple Gramnegative and Gram-positive pathogens. In this study, we demonstrate that brilacidin causes membrane depolarization in the Gram-positive bacterium Staphylococcus aureus, to an extent comparable to that caused by the lipopeptidic drug daptomycin. Transcriptional profiling of Staphylococcus aureus by deep sequencing shows that the global response to brilacidin treatment is well correlated to those of treatment with daptomycin and the cationic antimicrobial peptide LL37 and mostly indicates abrogation of cell wall and membrane functions. Furthermore, the upregulation of various chaperones and proteases by brilacidin and daptomycin indicates that cytoplasmic protein misfolding stress may be a contributor to the mechanism of action of these drugs. These stress responses were orchestrated mainly by three two-component systems, GraSR, VraSR, and NsaSR, which have been implicated in virulence and drug resistance against other clinically available antibiotics. The recent rise of multidrug-resistant pathogenic bacteria is an alarming health care crisis that has outpaced the discovery of effective and novel therapeutics (1, 2). Antimicrobial peptides (AMPs), which are evolutionarily conserved, first-line host defense mechanisms, offer an attractive platform for the development of new antibiotics (3-5). Most AMPs are believed to interact with bacterial membranes and cause cell death by dysregulating the properties of the phospholipid bilayer or by causing membrane leakage, although some have been identified to have downstream cytoplasmic targets as well (6). Despite the variety of sequences and secondary and tertiary structures, most AMPs share an amphiphilic topology, with a charged, mostly positive face that allows for interaction with the negatively charged bacterial membrane and a hydrophobic face that allows for insertion into the membrane and interaction with the apolar acyl chains of the bilayer (4, 7-10). Several mechanisms have been suggested for the nature of this interaction with the membrane, including carpet, toroidal pore, and barrel stave mechanisms (6). Development of resistance to these peptides is limited (11), presumably due to the membrane being the primary target (12). As such, several strategies have been employed to mimic the activity of AMPs in order to improve efficacy, selectivity for bacteria, and bioavailability while circumventing issues associated with peptidic drugs, such as proteolytic degradation and difficulties with large-scale synthesis. These include the use of scaffolds such as D-L peptides, ␤-amino acid helices, and antimicrobial polymers (13-15).In previous work, we developed a series of small-molecule arylamide mimics of AMPs that showed potent activity against a broad range of drug-susceptible and multidrug-resistant Gramnegative and Gram-positive bacteria (15-19). These compounds feature a small arylamide backbone that is stabilized by intramolecular hydroge...

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Section: Discussionsupporting

confidence: 79%

Comparative Mechanistic Studies of Brilacidin, Daptomycin, and the Antimicrobial Peptide LL16

Mensa

Howell

Scott³

et al. 2014

Antimicrob Agents Chemother

161

155

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“…Interestingly, serial passage of S. aureus in sub-inhibitory concentrations of DAP generated a derivative in which VraSR was upregulated and exhibited both VISA and DAP-nonsusceptible (DNS) phenotypes, further suggesting that VraSR responds to broad perturbations of the cell wall and cell membrane [21]. Similarly, mutations in vraSR can influence susceptibility to both vancomycin and β-lactams [22]. Moreover, dysregulation of the vraSR operon have been shown to affect methicillin and DAP susceptibility in clinical isolates of methicillin-resistant S. aureus (MRSA) [12, 23].…”

Section: Liafsr System As a Master Regulator Of The Cell Membrane Strmentioning

confidence: 99%

Targeting cell membrane adaptation as a novel antimicrobial strategy

Tran

Miller

Shamoo

et al. 2016

Current Opinion in Microbiology

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Emergence of antibiotic resistance is an example of the incredible plasticity of bacteria to survive in all environments. The search for new antibiotics active against traditional targets is more challenging due not only to the lack of novel natural products to fulfill the current clinical needs against multidrug-resistant (MDR) bacteria, but also for the possible “collateral” effects on the human microbiota. Thus, non-traditional approaches to combat MDR bacteria have been proposed. Here, we discuss the possibility of targeting the membrane response to the antibiotic attack (cell membrane adaptation) as a viable strategy to increase the activity of current antimicrobials, enhance the activity of the innate immune system and prevent development of resistance during therapy using the three-component regulatory system LiaFSR of enterococci as a model.

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“…Transcriptome and proteome analyses of MRSA isolates have revealed a link between nucleotide sequence variations of several genes and vancomycin resistance. 6 , 7 These genes include those of the two-component systems, such as vraRS , graRS or walRK , 6 , 8 , 9 and those involved in cell wall synthesis, such as upps , fmtC and srtA . 9 – 11 Single-nucleotide variations (SNVs) of genes related to antibiotic resistance have also been described.…”

Section: Introductionmentioning

confidence: 99%

“… 6 , 7 These genes include those of the two-component systems, such as vraRS , graRS or walRK , 6 , 8 , 9 and those involved in cell wall synthesis, such as upps , fmtC and srtA . 9 – 11 Single-nucleotide variations (SNVs) of genes related to antibiotic resistance have also been described. 8 , 9 , 12 , 13 These SNVs may allow differentiation between vancomycin-sensitive S. aureus (VSSA) and VISA.…”

Section: Introductionmentioning

confidence: 99%

Novel single-nucleotide variations associated with vancomycin resistance in vancomycin-intermediate <em>Staphylococcus aureus</em>

Lin¹,

Chang²,

Ge³

et al. 2018

IDR

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Prolonged vancomycin usage may cause methicillin-resistant Staphylococcus aureus to become vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA). Mechanisms of vancomycin resistance of VISA and hVISA are still unclear. In this study, analyses of nucleotide sequence variations in 30 vancomycin-sensitive S. aureus (VSSA), 41 hVISA and 16 VISA isolates revealed 29 single-nucleotide variations in 12 genes (fmtC, graR, graS, htrA, mecA, pbp2, pbp4, srtA, tcaA, upps, vicK and vraR) that are related to cell wall synthesis or the two-component system. Six of these 29 single-nucleotide variations were novel and resulted in the following amino acid changes: Q692E in FmtC; T278I, P306L and I311T in HtrA; and I63V and K101E in Upps. Since P306L and I311T in HtrA and I63V in Upps were present in the majority (76.7%–86.7%) of VSSA isolates, these three amino acid variations may not be associated with vancomycin resistance. The other three amino acid variations (T278I in HtrA, K101E in Upps and Q692E in FmtC) were present in the majority (87.5%–93.8%) of hVISA and VISA isolates, but only in a small number (22.9%–25.7%) of VSSA isolates, suggesting that they are associated with vancomycin resistance.

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Prevalence of amino acid changes in the yvqF, vraSR, graSR, and tcaRAB genes from vancomycin intermediate resistant Staphylococcus aureus

Cited by 27 publications

References 22 publications

Comparative Mechanistic Studies of Brilacidin, Daptomycin, and the Antimicrobial Peptide LL16

Comparative Mechanistic Studies of Brilacidin, Daptomycin, and the Antimicrobial Peptide LL16

Targeting cell membrane adaptation as a novel antimicrobial strategy

Novel single-nucleotide variations associated with vancomycin resistance in vancomycin-intermediate <em>Staphylococcus aureus</em>

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