scholarly journals Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

2005 ◽  
Vol 49 (3) ◽  
pp. 1127-1134 ◽  
Author(s):  
Deborah L. Higgins ◽  
Ray Chang ◽  
Dmitri V. Debabov ◽  
Joey Leung ◽  
Terry Wu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Membrane Potential ◽  
Cell Membrane ◽  
Bactericidal Activity ◽  
Bacterial Cell ◽  
Cell Membrane Potential ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Bacterial Cell Membrane

ABSTRACTThe emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptideN,N′-diacetyl-l-lysinyl-d-alanyl-d-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistantStaphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K+. The timing of these changes correlated with rapid , concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.

scholarly journals Rhodomyrtone Accumulates in Bacterial Cell Wall and Cell Membrane and Inhibits the Synthesis of Multiple Cellular Macromolecules in Epidemic Methicillin-Resistant Staphylococcus aureus

Antibiotics ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 543
Author(s):  
Ozioma F. Nwabor ◽  
Sukanlaya Leejae ◽  
Supayang P. Voravuthikunchai
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Membrane ◽  
Bacterial Cell ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Treatment Options ◽  
Bacterial Cell Wall ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Inhibitor Compounds

As the burden of antibacterial resistance worsens and treatment options become narrower, rhodomyrtone—a novel natural antibiotic agent with a new antibacterial mechanism—could replace existing antibiotics for the treatment of infections caused by multi-drug resistant Gram-positive bacteria. In this study, rhodomyrtone was detected within the cell by means of an easy an inexpensive method. The antibacterial effects of rhodomyrtone were investigated on epidemic methicillin-resistant Staphylococcus aureus. Thin-layer chromatography demonstrated the entrapment and accumulation of rhodomyrtone within the bacterial cell wall and cell membrane. The incorporation of radiolabelled precursors revealed that rhodomyrtone inhibited the synthesis of macromolecules including DNA, RNA, proteins, the cell wall, and lipids. Following the treatment with rhodomyrtone at MIC (0.5–1 µg/mL), the synthesis of all macromolecules was significantly inhibited (p ≤ 0.05) after 4 h. Inhibition of macromolecule synthesis was demonstrated after 30 min at a higher concentration of rhodomyrtone (4× MIC), comparable to standard inhibitor compounds. In contrast, rhodomyrtone did not affect lipase activity in staphylococci—both epidemic methicillin-resistant S. aureus and S. aureus ATCC 29213. Interfering with the synthesis of multiple macromolecules is thought to be one of the antibacterial mechanisms of rhodomyrtone.

Lupinifolin from Derris reticulata possesses bactericidal activity on Staphylococcus aureus by disrupting bacterial cell membrane

2016 ◽  
Vol 71 (2) ◽  
pp. 357-366 ◽  
Author(s):  
Kamol Yusook ◽  
Oratai Weeranantanapan ◽  
Yanling Hua ◽  
Pakarang Kumkrai ◽  
Nuannoi Chudapongse
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Membrane ◽  
Bactericidal Activity ◽  
Bacterial Cell ◽  
Bacterial Cell Membrane ◽  
Derris Reticulata

Design of bio-molecular interfaces using liquid crystals demonstrating endotoxin interactions with bacterial cell wall components

RSC Advances ◽  
2015 ◽  
Vol 5 (81) ◽  
pp. 66476-66486 ◽  
Author(s):  
Dibyendu Das ◽  
Sumyra Sidiq ◽  
Santanu Kumar Pal
Keyword(s):  
Cell Wall ◽  
Liquid Crystals ◽  
Cell Membrane ◽  
Bacterial Cell ◽  
Bacterial Cell Wall ◽  
Cell Wall Components ◽  
Bacterial Cell Membrane ◽  
Membrane Components ◽  
Wall Components

Liquid crystals offer a promising approach to study and quantify the interactions between different bacterial cell membrane components with endotoxin at an aqueous interface.

scholarly journals Signaling mechanism by the Staphylococcus aureus two-component system LytSR: role of acetyl phosphate in bypassing the cell membrane electrical potential sensor LytS

F1000Research ◽  
2016 ◽  
Vol 4 ◽  
pp. 79 ◽  
Author(s):  
Kevin Patel ◽  
Dasantila Golemi-Kotra
Keyword(s):  
Staphylococcus Aureus ◽  
Membrane Potential ◽  
Cell Membrane ◽  
Electrical Potential ◽  
Cell Membrane Potential ◽  
Acetyl Phosphate ◽  
Two Component System ◽  
Component System ◽  
Two Component ◽  
Membrane Electrical Potential

The two-component system LytSR has been linked to the signal transduction of cell membrane electrical potential perturbation and is involved in the adaptation of Staphylococcus aureus to cationic antimicrobial peptides. It consists of a membrane-bound histidine kinase, LytS, which belongs to the family of multiple transmembrane-spanning domains receptors, and a response regulator, LytR, which belongs to the novel family of non-helix-turn-helix DNA-binding domain proteins. LytR regulates the expression of cidABC and lrgAB operons, the gene products of which are involved in programmed cell death and lysis. In vivo studies have demonstrated involvement of two overlapping regulatory networks in regulating the lrgAB operon, both depending on LytR. One regulatory network responds to glucose metabolism and the other responds to changes in the cell membrane potential. Herein, we show that LytS has autokinase activity and can catalyze a fast phosphotransfer reaction, with 50% of its phosphoryl group lost within 1 minute of incubation with LytR. LytS has also phosphatase activity. Notably, LytR undergoes phosphorylation by acetyl phosphate at a rate that is 2-fold faster than the phosphorylation by LytS. This observation is significant in lieu of the in vivo observations that regulation of the lrgAB operon is LytR-dependent in the presence of excess glucose in the medium. The latter condition does not lead to perturbation of the cell membrane potential but rather to the accumulation of acetate in the cell. Our study provides insights into the molecular basis for regulation of lrgAB in a LytR-dependent manner under conditions that do not involve sensing by LytS.

scholarly journals Altering the Proclivity towards Daptomycin Resistance in Methicillin-Resistant Staphylococcus aureus Using Combinations with Other Antibiotics

2012 ◽  
Vol 56 (10) ◽  
pp. 5046-5053 ◽  
Author(s):  
Andrew D. Berti ◽  
Justine E. Wergin ◽  
Gary G. Girdaukas ◽  
Scott J. Hetzel ◽  
George Sakoulas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Membrane ◽  
Membrane Integrity ◽  
Wall Thickening ◽  
Methicillin Resistant ◽  
Content Type ◽  
Cell Membrane Integrity ◽  
Cell Membrane Fluidity

ABSTRACTDaptomycin (DAP) is increasingly used as a part of combination therapy, particularly in complex methicillin-resistantStaphylococcus aureus(MRSA) infections. While multiple studies have reported the potential for synergy between DAP and adjunctive anti-infectives, few have examined the influence of adjunctive therapy on the emergence of DAP resistance. This study examined eight adjunctive antimicrobial combinations with DAPin vitroand the emergence of DAP resistance over time (up to 4 weeks) using clinical isolates of DAP-susceptible MRSA (MIC, 0.5 μg/ml) in which DAP resistance subsequently developed during patient therapy (MIC, 3 μg/ml). In addition to DAP susceptibility testing, selected strains were examined for phenotypic changes associated with DAP resistance, including changes to cell wall thickness (CWT) and cell membrane alterations. The addition of either oxacillin or clarithromycin in medium containing DAP significantly inhibited the development of DAP resistance through the entirety of the 4-week exposure (10- to 32-fold MIC reduction from that of DAP alone). Combinations with rifampin or fosfomycin were effective in delaying the emergence of DAP resistance through the end of week one only (week one MIC, 0.5 μg/ml; week four MIC, 24 μg/ml). Cell wall thickening was observed for all antibiotic combinations regardless of their effect on the DAP MIC (14 to 70% increase in CWT), while changes in cell membrane fluidity were variable and treatment dependent. DAP showed reduced activity against strains with DAP MICs of 1 to 12 μg/ml, but cell membrane integrity was still disrupted at concentrations achieved with doses greater than 10 mg/kg of body weight. The emergence of DAP resistance in MRSA is strongly influenced by the presence of subinhibitory concentrations of adjunctive antimicrobials. These data suggest that combining DAP with oxacillin or clarithromycin may delay the development of DAP resistance in cases requiring prolonged antibiotic therapy.

scholarly journals In VitroCross-Resistance to Daptomycin and Host Defense Cationic Antimicrobial Peptides in Clinical Methicillin-Resistant Staphylococcus aureus Isolates

2011 ◽  
Vol 55 (9) ◽  
pp. 4012-4018 ◽  
Author(s):  
Nagendra N. Mishra ◽  
James McKinnell ◽  
Michael R. Yeaman ◽  
Aileen Rubio ◽  
Cynthia C. Nast ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Membrane ◽  
Antimicrobial Peptides ◽  
Surface Charge ◽  
Host Defense ◽  
Cationic Antimicrobial Peptides ◽  
Methicillin Resistant ◽  
Membrane Order

ABSTRACTWe investigated the hypothesis that methicillin-resistantStaphylococcus aureus(MRSA) isolates developing reduced susceptibilities to daptomycin (DAP; a calcium-dependent molecule acting as a cationic antimicrobial peptide [CAP]) may also coevolve reducedin vitrosusceptibilities to host defense cationic antimicrobial peptides (HDPs). Ten isogenic pairs of clinical MRSA DAP-susceptible/DAP-resistant (DAPs/DAPr) strains were tested against two distinct HDPs differing in structure, mechanism of action, and origin (thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]) and one bacterium-derived CAP, polymyxin B (PMB). Seven of 10 DAPrstrains had point mutations in themprFlocus (with or withoutyycoperon mutations), while three DAPrstrains had neither mutation. Several phenotypic parameters previously associated with DAPrwere also examined: cell membrane order (fluidity), surface charge, and cell wall thickness profiles. Compared to the 10 DAPsparental strains, their respective DAPrstrains exhibited (i) significantly reduced susceptibility to killing by all three peptides (P< 0.05), (ii) increased cell membrane fluidity, and (iii) significantly thicker cell walls (P< 0.0001). There was no consistent pattern of surface charge profiles distinguishing DAPsand DAPrstrain pairs. Reducedin vitrosusceptibility to two HDPs and one bacterium-derived CAP tracked closely with DAPrin these 10 recent MRSA clinical isolates. These results suggest that adaptive mechanisms involved in the evolution of DAPralso provide MRSA with enhanced survivability against HDPs. Such adaptations appear to correlate with MRSA variations in cell membrane order and cell wall structure. DAPrstrains with or without mutations in themprFlocus demonstrated significant cross-resistance profiles to these unrelated CAPs.

scholarly journals Potency and Bactericidal Activity of Iclaprim against Recent Clinical Gram-Positive Isolates

2009 ◽  
Vol 53 (5) ◽  
pp. 2171-2175 ◽  
Author(s):  
Helio S. Sader ◽  
Thomas R. Fritsche ◽  
Ronald N. Jones
Keyword(s):  
United States ◽  
Staphylococcus Aureus ◽  
Enterococcus Faecalis ◽  
Bactericidal Activity ◽  
The United States ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Gram Positive ◽  
Methicillin Resistant

ABSTRACT The in vitro activity of iclaprim, a novel diaminopyrimidine derivative, was evaluated against 5,937 recent gram-positive clinical isolates collected in the United States and Europe. Iclaprim demonstrated potent activity against Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]), beta-hemolytic Streptococcus spp., and Enterococcus faecalis strains tested. In addition, iclaprim exhibited bactericidal activity against all S. aureus strains tested, including MRSA.

scholarly journals The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Maytham Hussein ◽  
John A. Karas ◽  
Elena K. Schneider-Futschik ◽  
Fan Chen ◽  
James Swarbrick ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Membrane Lipids ◽  
Cell Envelope ◽  
Teichoic Acid ◽  
Bacterial Membrane ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Content Type ◽  
Metabolomics Study

ABSTRACT Antibiotics have served humankind through their use in modern medicine as effective treatments for otherwise fatal bacterial infections. Teixobactin is a first member of newly discovered natural antibiotics that was recently identified from a hitherto-unculturable soil bacterium, Eleftheria terrae, and recognized as a potent antibacterial agent against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. The most distinctive characteristic of teixobactin as an effective antibiotic is that teixobactin resistance could not be evolved in a laboratory setting. It is purported that teixobactin’s “resistance-resistant” mechanism of action includes binding to the essential bacterial cell wall synthesis building blocks lipid II and lipid III. In the present study, metabolomics was used to investigate the potential metabolic pathways involved in the mechanisms of antibacterial activity of the synthetic teixobactin analogue Leu10-teixobactin against a MRSA strain, S. aureus ATCC 700699. The metabolomes of S. aureus ATCC 700699 cells 1, 3, and 6 h following treatment with Leu10-teixobactin (0.5 μg/ml, i.e., 0.5× MIC) were compared to those of the untreated controls. Leu10-teixobactin significantly perturbed bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan (lipid I and II) metabolism, and cell wall teichoic acid (lipid III) biosynthesis as early as after 1 h of treatment, reflecting an initial activity on the cell envelope. Concordant with its time-dependent antibacterial killing action, Leu10-teixobactin caused more perturbations in the levels of key intermediates in pathways of amino-sugar and nucleotide-sugar metabolism and their downstream peptidoglycan and teichoic acid biosynthesis at 3 and 6 h. Significant perturbations in arginine metabolism and the interrelated tricarboxylic acid cycle, histidine metabolism, pantothenate, and coenzyme A biosynthesis were also observed at 3 and 6 h. To conclude, this is the first study to provide novel metabolomics mechanistic information, which lends support to the development of teixobactin as an antibacterial drug for the treatment of multidrug-resistant Gram-positive infections. IMPORTANCE Antimicrobial resistance is one of the greatest threats to the global health system. It is imperative that new anti-infective therapeutics be developed against problematic “superbugs.” The cyclic depsipeptide teixobactin holds much promise as a new class of antibiotics for highly resistant Gram-positive pathogens (e.g., methicillin-resistant Staphylococcus aureus [MRSA]). Understanding its molecular mechanism(s) of action could lead to the design of new compounds with a broader activity spectrum. Here, we describe the first metabolomics study to investigate the killing mechanism(s) of teixobactin against MRSA. Our findings revealed that teixobactin significantly disorganized the bacterial cell envelope, as reflected by a profound perturbation in the bacterial membrane lipids and cell wall biosynthesis (peptidoglycan and teichoic acid). Importantly, teixobactin significantly suppressed the main intermediate d-alanyl-d-lactate involved in the mechanism of vancomycin resistance in S. aureus. These novel results help explain the unique mechanism of action of teixobactin and its lack of cross-resistance with vancomycin.

Sign in / Sign up

Export Citation Format

Share Document