<i>In Vitro</i>
            Cross-Resistance to Daptomycin and Host Defense Cationic Antimicrobial Peptides in Clinical Methicillin-Resistant Staphylococcus aureus Isolates

Mishra, Nagendra N.; McKinnell, James A.; Yeaman, Michael R.; Rubio, Aileen; Nast, Cynthia C.; Chen, Liang; Kreiswirth, Barry N.; Bayer, Arnold S.

doi:10.1128/aac.00223-11

Cited by 126 publications

(189 citation statements)

References 47 publications

Supporting

Mentioning

173

Contrasting

Unclassified

Order By: Relevance

“…108,109 in vitro -derived resistant mutants of Staphylococcus aureus exhibited changes affecting the histidine kinase of the system (YycG). 110,111 In Bacillus subtilis, this protein is located at the cell division septum, where it regulates cell division and wall restructuring. 112 Several mutations in different locations of the yycFG operon in daptomycinresistant S. aureus were reported by Howden et al, although their exact contribution to resistance is unclear.…”

Section: Mutations In the Yycfg Operonmentioning

confidence: 99%

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

237

172

View full text Add to dashboard Cite

Daptomycin is a lipopeptide antibiotic produced by the soil bacterium Streptomyces roseosporus that is clinically used to treat severe infections with Grampositive bacteria. In this review, we discuss the mode of action of this important antibiotic. Although daptomycin is structurally related to amphomycin and similar lipopeptides that inhibit peptidoglycan biosynthesis, experimental studies have not produced clear evidence that daptomycin shares their action mechanism. Instead, the best characterized effect of daptomycin is the permeabilization and depolarization of the bacterial cell membrane. This activity, which can account for daptomycin's bactericidal effect, correlates with the level of phosphatidylglycerol (PG) in the membrane. Accordingly, reduced synthesis of PG or its increased conversion to lysyl-PG promotes bacterial resistance to daptomycin. While other resistance mechanisms suggest that daptomycin may indeed directly interfere with cell wall synthesis or cell division, such effects still await direct experimental confirmation. Daptomycin's complex structure and biosynthesis have hampered the analysis of its structure activity relationships. Novel methods of total synthesis, including a recent one that is carried out entirely on a solid phase, will enable a more thorough and systematic exploration of the sequence space.

show abstract

Section: Mutations In the Yycfg Operonmentioning

confidence: 99%

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

237

172

View full text Add to dashboard Cite

show abstract

“…Although the precise mechanisms are not clear, the degree of cell wall thickness of S. aureus is felt to play an important role in resistance to VAN killing (24). Therefore, MRSA strains were assessed for cell wall thickness by transmission electron microscopy (25,26). For each MRSA strain, the cell wall thickness of 100 individual cells was measured at 190,000ϫ magnification (model 100CX; JEOL, Tokyo, Japan), and data were analyzed to determine mean cell wall thickness (Ϯ SD).…”

Section: Methodsmentioning

confidence: 99%

Reduced Vancomycin Susceptibility in anIn VitroCatheter-Related Biofilm Model Correlates with Poor Therapeutic Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

Abdelhady

Bayer

Seidl

et al. 2013

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

“…The persistence and progression of endovascular S. aureus infections, such as infective endocarditis (IE), necessitate the pathogen to resist the microbicidal actions of HD-CAPs (6,8), including those of PMNs (e.g., neutrophil defensins, such as hNP-1) and platelets (e.g., the family of thrombin-induced platelet microbicidal proteins [tPMPs]), as well as clinically utilized CAPs (e.g., calcium-daptomycin). Of importance, S. aureus appears to deploy a number of mechanisms to subvert inhibition or killing by HD-CAPs, including changes in cytoplasmic membrane (CM) biophysics or energetics, perturbations in surface charge, and modifications of the phospholipid repertoire (9)(10)(11)(12).…”

mentioning

confidence: 99%

Site-Specific Mutation of the Sensor Kinase GraS in Staphylococcus aureus Alters the Adaptive Response to Distinct Cationic Antimicrobial Peptides

et al. 2014

Self Cite

View full text Add to dashboard Cite

The Staphylococcus aureus two-component regulatory system, GraRS, is involved in resistance to killing by distinct host defense cationic antimicrobial peptides (HD-CAPs). It is believed to regulate downstream target genes such as mprF and dltABCD to modify the S. aureus surface charge. However, the detailed mechanism(s) by which the histidine kinase, GraS, senses specific HD-CAPs is not well defined. Here, we studied a well-characterized clinical methicillin-resistant S. aureus (MRSA) strain (MW2), its isogenic graS deletion mutant (⌬graS strain), a nonameric extracellular loop mutant (⌬EL strain), and four residuespecific ⌬EL mutants (D37A, P39A, P39S, and D35G D37G D41G strains). The ⌬graS and ⌬EL strains were unable to induce mprF and dltA expression and, in turn, demonstrated significantly increased susceptibilities to daptomycin, polymyxin B, and two prototypical HD-CAPs (hNP-1 and RP-1). Further, P39A, P39S, and D35G-D37G-D41G ⌬EL mutations correlated with moderate increases in HD-CAP susceptibility. Reductions of mprF and dltA induction by PMB were also found in the ⌬EL mutants, suggesting these residues are pivotal to appropriate activation of the GraS sensor kinase. Importantly, a synthetic exogenous soluble EL mimic of GraS protected the parental MW2 strain against hNP-1-and RP-1-mediated killing, suggesting a direct interaction of the EL with HD-CAPs in GraS activation. In vivo, the ⌬graS and ⌬EL strains displayed dramatic reductions in achieved target tissue MRSA counts in an endocarditis model. Taken together, our results provide new insights into potential roles of GraS in S. aureus sensing of HD-CAPs to induce adaptive survival responses to these molecules.

show abstract

In Vitro Cross-Resistance to Daptomycin and Host Defense Cationic Antimicrobial Peptides in Clinical Methicillin-Resistant Staphylococcus aureus Isolates

Abstract: We investigated the hypothesis that methicillin-resistant

Cited by 126 publications

References 47 publications

The action mechanism of daptomycin

The action mechanism of daptomycin

Reduced Vancomycin Susceptibility in anIn VitroCatheter-Related Biofilm Model Correlates with Poor Therapeutic Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

Site-Specific Mutation of the Sensor Kinase GraS in Staphylococcus aureus Alters the Adaptive Response to Distinct Cationic Antimicrobial Peptides

Contact Info

Product

Resources

About