scholarly journals A Small Membrane Stabilizing Protein Critical to the Pathogenicity of Staphylococcus aureus

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
Seána Duggan ◽  
Maisem Laabei ◽  
Alaa Abdulaziz Alnahari ◽  
Eóin C. O’Brien ◽  
Keenan A. Lacey ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Iron Homeostasis ◽  
Control Strategies ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Promising Target ◽  
Significant Impairment ◽  
The Stability ◽  
Conventional Antibiotics ◽  
And Control

ABSTRACT Staphylococcus aureus is a major human pathogen, and the emergence of antibiotic-resistant strains is making all types of S. aureus infections more challenging to treat. With a pressing need to develop alternative control strategies to use alongside or in place of conventional antibiotics, one approach is the targeting of established virulence factors. However, attempts at this have had little success to date, suggesting that we need to better understand how this pathogen causes disease if effective targets are to be identified. To address this, using a functional genomics approach, we have identified a small membrane-bound protein that we have called MspA. Inactivation of this protein results in the loss of the ability of S. aureus to secrete cytolytic toxins, protect itself from several aspects of the human innate immune system, and control its iron homeostasis. These changes appear to be mediated through a change in the stability of the bacterial membrane as a consequence of iron toxicity. These pleiotropic effects on the ability of the pathogen to interact with its host result in significant impairment in the ability of S. aureus to cause infection in both a subcutaneous and sepsis model of infection. Given the scale of the effect the inactivation of MspA causes, it represents a unique and promising target for the development of a novel therapeutic approach.

scholarly journals A small membrane protein critical to both the offensive and defensive capabilities of Staphylococcus aureus

2019 ◽  
Author(s):  
Seána Duggan ◽  
Maisem Laabei ◽  
Alaa Alnahari ◽  
Eóin C. O’Brien ◽  
Keenan A. Lacey ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune System ◽  
Membrane Protein ◽  
Iron Homeostasis ◽  
Treatment Strategies ◽  
Population Level ◽  
Toxin Production ◽  
Effective Control ◽  
Significant Impairment ◽  
The Stability

AbstractStaphylococcus aureus is a major human pathogen, where the widespread emergence of antibiotic resistance is making infections more challenging to treat. Toxin induced tissue damage and resistance to the host’s immune system are well established as critical to its ability to cause disease. However, recent attempts to study S. aureus pathogenicity at a population level have revealed significant complexity and hierarchical levels of regulation. In an effort to better understand this we have identified and characterized a principle effector protein, MasA. The inactivation of this small highly-conserved membrane protein simultaneously disrupts toxin production and impairs S. aureus’ ability to resist several aspects of the innate immune system. These pleiotropic effects are mediated by both a change in the stability of the bacterial membrane and the dysregulation of iron homeostasis, which results in a significant impairment in the ability of S. aureus to cause infection in both a subcutaneous and a sepsis model of infection. That proteins with such major effects on pathogenicity remain unidentified in a bacterium as well studied as S. aureus demonstrates how incomplete our understanding of their ability to cause disease is, an issue that needs to be addressed if effective control and treatment strategies are to be developed.

scholarly journals Inhibition of Staphylococcus aureus Invasion into Bovine Mammary Epithelial Cells by Contact with Live Lactobacillus casei

2012 ◽  
Vol 79 (3) ◽  
pp. 877-885 ◽  
Author(s):  
Damien S. Bouchard ◽  
Lucie Rault ◽  
Nadia Berkova ◽  
Yves Le Loir ◽  
Sergine Even
Keyword(s):  
Staphylococcus Aureus ◽  
Epithelial Cells ◽  
Lactobacillus Casei ◽  
Mammary Epithelial Cells ◽  
Control Strategies ◽  
Mammary Epithelial ◽  
Dairy Herds ◽  
Dependent Manner ◽  
Content Type ◽  
Bovine Mammary Epithelial Cells

ABSTRACTStaphylococcus aureusis a major pathogen that is responsible for mastitis in dairy herds.S. aureusmastitis is difficult to treat and prone to recurrence despite antibiotic treatment. The ability ofS. aureusto invade bovine mammary epithelial cells (bMEC) is evoked to explain this chronicity. One sustainable alternative to treat or prevent mastitis is the use of lactic acid bacteria (LAB) as mammary probiotics. In this study, we tested the ability ofLactobacillus caseistrains to prevent invasion of bMEC by twoS. aureusbovine strains, RF122 and Newbould305, which reproducibly induce acute and moderate mastitis, respectively.L. caseistrains affected adhesion and/or internalization ofS. aureusin a strain-dependent manner. Interestingly,L. caseiCIRM-BIA 667 reducedS. aureusNewbould305 and RF122 internalization by 60 to 80%, and this inhibition was confirmed for two otherL. caseistrains, including one isolated from bovine teat canal. The protective effect occurred without affecting bMEC morphology and viability. Once internalized, the fate ofS. aureuswas not affected byL. casei. It should be noted thatL. caseiwas internalized at a low rate but survived in bMEC cells with a better efficiency than that ofS. aureusRF122. Inhibition ofS. aureusadhesion was maintained with heat-killedL. casei, whereas contact between liveL. caseiandS. aureusor bMEC was required to preventS. aureusinternalization. This first study of the antagonism of LAB towardS. aureusin a mammary context opens avenues for the development of novel control strategies against this major pathogen.

scholarly journals Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (11) ◽  
pp. 5325-5330 ◽  
Author(s):  
Yan Q. Xiong ◽  
Wessam Abdel Hady ◽  
Antoine Deslandes ◽  
Astrid Rey ◽  
Laurent Fraisse ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Maximum Effect ◽  
Peptide Antibiotic ◽  
Time Curve ◽  
Cationic Antimicrobial Peptide ◽  
Unbound Fraction ◽  
Methicillin Resistant ◽  
Content Type ◽  
Conventional Antibiotics

ABSTRACTCationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungusPseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) thein vivopharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) thein vivoefficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistantStaphylococcus aureus(MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin (P< 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. Thesein vivoefficacies were equivalent and significantly correlated with three PK indices investigated:fCmax/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC),fAUC/MIC (where AUC is the area under the concentration-time curve), andf%T>MIC(%T>MICis the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (Emax) model (R2> 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.

scholarly journals Risk Factors for Infection or Colonization with CTX-M Extended-Spectrum-β-Lactamase-Positive Escherichia coli

2012 ◽  
Vol 56 (11) ◽  
pp. 5575-5580 ◽  
Author(s):  
Jennifer H. Han ◽  
Kei Kasahara ◽  
Paul H. Edelstein ◽  
Warren B. Bilker ◽  
Ebbing Lautenbach
Keyword(s):  
Risk Factors ◽  
Escherichia Coli ◽  
Control Strategies ◽  
Content Type ◽  
E Coli ◽  
Extended Spectrum ◽  
Increased Risk ◽  
Urinary Culture ◽  
Multivariable Analyses ◽  
And Control

ABSTRACTThere has been a significant increase in the prevalence ofEnterobacteriaceaethat produce CTX-M-type extended-spectrum β-lactamases. The objective of this study was to evaluate risk factors for infection or colonization with CTX-M-positiveEscherichia coli. A case-control study was conducted within a university system from 1 January 2007 to 31 December 2008. All patients with clinical cultures withE. colidemonstrating resistance to extended-spectrum cephalosporins were included. Case patients were designated as those with cultures positive for CTX-M-positiveE. coli, and control patients were designated as those with non-CTX-M-producingE. coli. Multivariable logistic regression analyses were performed to evaluate risk factors for CTX-M-positive isolates. A total of 83 (56.8%) of a total of 146 patients had cultures with CTX-M-positiveE. coli. On multivariable analyses, there was a significant association between infection or colonization with CTX-M-type β-lactamase-positiveE. coliand receipt of piperacillin-tazobactam in the 30 days prior to the culture date (odds ratio [OR], 7.36; 95% confidence interval [CI], 1.61 to 33.8;P= 0.01) and a urinary culture source (OR, 0.36; 95% CI, 0.17 to 0.77;P= 0.008). The rates of resistance to fluoroquinolones were significantly higher in isolates from case patients than in isolates from control patients (90.4 and 50.8%, respectively;P< 0.001). We found that nonurinary sources of clinical cultures and the recent use of piperacillin-tazobactam conferred an increased risk of colonization or infection with CTX-M-positiveE. coli. Future studies will need to focus on outcomes associated with infections due to CTX-M-positiveE. coli, as well as infection control strategies to limit the spread of these increasingly common organisms.

Development of a soft cable-driven hand exoskeleton for assisted rehabilitation training

2020 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Dawen Xu ◽  
Qingcong Wu ◽  
Yanghui Zhu
Keyword(s):  
Muscle Activation ◽  
Control Strategies ◽  
Motor Dysfunction ◽  
Force Transmission ◽  
Content Type ◽  
Rehabilitation Training ◽  
Local Structures ◽  
Hand Exoskeleton ◽  
And Control

Purpose Hand motor dysfunction has seriously reduced people’s quality of life. The purpose of this paper is to solve this problem; different soft exoskeleton robots have been developed because of their good application prospects in assistance. In this paper, a new soft hand exoskeleton is designed to help people conduct rehabilitation training. Design/methodology/approach The proposed soft exoskeleton is an under-actuated cable-driven mechanism, which optimizes the force transmission path and many local structures. Specifically, the path of force transmission is optimized and cables are wound around cam-shaped spools to prevent cables lose during fingers movement. Besides, a pre-tightening system is presented to adjust the preload force of the cable-tube. Moreover, a passive brake mechanism is proposed to prevent the cables from falling off the spools when the remote side is relaxed. Findings Finally, three control strategies are proposed to assist in rehabilitation training. Results show that the average correlation coefficient of trajectory tracking is 90.99% and this exoskeleton could provide steady clamping force up to 35 N, which could meet the demands of activities in daily living. Surface electromyography (sEMG)-based intention recognition method is presented to complete assistance and experiments are conducted to prove the effectiveness of the assisted grasping method by monitoring muscle activation, finger angle and interactive force. Research limitations/implications However, the system should be further optimized in terms of hardware and control to reduce delays. In addition, more clinical trials should be conducted to evaluate the effect of the proposed rehabilitation strategies. Social implications May improve the ability of hemiplegic patients to live independently. Originality/value A novel under-actuated soft hand exoskeleton structure is proposed, and an sEMG-based auxiliary grasping control strategy is presented to help hemiplegic patients conduct rehabilitation training.

scholarly journals A novel steady-state maintenance simulation framework for multi- information disseminations in crowd network

2020 ◽  
Vol 4 (3) ◽  
pp. 273-282
Author(s):  
Zhong Wang ◽  
Hongbo Sun ◽  
Baode Fan
Keyword(s):  
Steady State ◽  
Design Methodology ◽  
Information Dissemination ◽  
Simulation Platform ◽  
Simulation Framework ◽  
Source Information ◽  
Content Type ◽  
General Rules ◽  
The Stability ◽  
And Control

Purpose The era of crowd network is coming and the research of its steady-state is of great importance. This paper aims to establish a crowd network simulation platform and maintaining the relative stability of multi-source dissemination systems. Design/methodology/approach With this simulation platform, this paper studies the characteristics of “emergence,” monitors the state of the system and according to the fixed point judges the system of steady-state conditions, then uses three control conditions and control methods to control the system status to acquire general rules for maintain the stability of multi-source information dissemination systems. Findings This paper establishes a novel steady-state maintenance simulation framework. It will be useful for achieving controllability to the evolution of information dissemination and simulating the effectiveness of control conditions for multi-source information dissemination systems. Originality/value This paper will help researchers to solve problems of public opinion control in multi-source information dissemination in crowd network.

scholarly journals Clearance of Staphylococcus aureus from In Vivo Models of Chronic Infection by Immunization Requires Both Planktonic and Biofilm Antigens

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Janette M. Harro ◽  
Yvonne Achermann ◽  
Jeffrey A. Freiberg ◽  
Devon L. Allison ◽  
Kristen J. Brao ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protective Efficacy ◽  
Passive Immunization ◽  
Quadrivalent Vaccine ◽  
Bacterial Populations ◽  
In Vivo Models ◽  
Content Type ◽  
Pentavalent Vaccine ◽  
And Control

ABSTRACT Staphylococcus aureus is a causative agent of chronic biofilm-associated infections that are recalcitrant to resolution by the immune system or antibiotics. To combat these infections, an antistaphylococcal, biofilm-specific quadrivalent vaccine against an osteomyelitis model in rabbits has previously been developed and shown to be effective at eliminating biofilm-embedded bacterial populations. However, the addition of antibiotics was required to eradicate remaining planktonic populations. In this study, a planktonic upregulated antigen was combined with the quadrivalent vaccine to remove the need for antibiotic therapy. Immunization with this pentavalent vaccine followed by intraperitoneal challenge of BALB/c mice with S. aureus resulted in 16.7% and 91.7% mortality in pentavalent vaccine and control groups, respectively (P < 0.001). Complete bacterial elimination was found in 66.7% of the pentavalent cohort, while only 8.3% of the control animals cleared the infection (P < 0.05). Further protective efficacy was observed in immunized rabbits following intramedullary challenge with S. aureus, where 62.5% of the pentavalent cohort completely cleared the infection, versus none of the control animals (P < 0.05). Passive immunization of BALB/c mice with serum IgG against the vaccine antigens prior to intraperitoneal challenge with S. aureus prevented mortality in 100% of mice and eliminated bacteria in 33.3% of the challenged mice. These results demonstrate that targeting both the planktonic and biofilm stages with the pentavalent vaccine or the IgG elicited by immunization can effectively protect against S. aureus infection.

scholarly journals Investigations on Vehicle Rollover Prevention Using LQG Regulator

2014 ◽  
Vol 2014 ◽  
pp. 1-11
Author(s):  
Binda Mridula Balakrishnan ◽  
Marimuthu Rajaram
Keyword(s):  
Control Strategies ◽  
Stability Margin ◽  
Initial Investigation ◽  
Rollover Prevention ◽  
Contact Information ◽  
Vehicle Rollover ◽  
The Stability ◽  
And Control

This paper presents results of an initial investigation into vehicle roll model and control strategies suitable for preventing vehicle untripped rollovers. For vehicles that are deemed to be susceptible to wheel-liftoff, various control strategies are implemented in simulation. In this study, the authors propose a method for rollover prevention that does not require such accurate contact information. The validity of the stability margin is shown, and it is used to realize rollover prevention in the direction of the roll. The primary assumption in their implementation is that the vehicle in question is equipped with a conventional controller system.

scholarly journals The 5′ NAD Cap of RNAIII Modulates Toxin Production in Staphylococcus aureus Isolates

2019 ◽  
Vol 202 (6) ◽  
Author(s):  
Hector Gabriel Morales-Filloy ◽  
Yaqing Zhang ◽  
Gabriele Nübel ◽  
Shilpa Elizabeth George ◽  
Natalya Korn ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Secondary Structure ◽  
Quorum Sensing ◽  
Opportunistic Pathogen ◽  
Toxin Production ◽  
Dual Function ◽  
Content Type ◽  
The Stability

ABSTRACT Nicotinamide adenosine dinucleotide (NAD) has been found to be covalently attached to the 5′ ends of specific RNAs in many different organisms, but the physiological consequences of this modification are largely unknown. Here, we report the occurrence of several NAD-RNAs in the opportunistic pathogen Staphylococcus aureus. Most prominently, RNAIII, a central quorum-sensing regulator of this bacterium’s physiology, was found to be 5′ NAD capped in a range from 10 to 35%. NAD incorporation efficiency into RNAIII was found to depend in vivo on the −1 position of the P3 promoter. An increase in RNAIII’s NAD content led to a decreased expression of alpha- and delta-toxins, resulting in reduced cytotoxicity of the modified strains. These effects seem to be caused neither by changes in RNAIII’s secondary structure nor by a different translatability upon NAD attachment, as indicated by unaltered patterns in in vitro chemical probing and toeprinting experiments. Even though we did not observe any effect of this modification on RNAIII’s secondary structure or translatability in vitro, additional unidentified factors might account for the modulation of exotoxins in vivo. Ultimately, the study constitutes a step forward in the discovery of new roles of the NAD molecule in bacteria. IMPORTANCE Numerous organisms, including bacteria, are endowed with a 5′ NAD cap in specific RNAs. While the presence of the 5′ NAD cap modulates the stability of the modified RNA species, a significant biological function and phenotype have not been assigned so far. Here, we show the presence of a 5′ NAD cap in RNAIII from S. aureus, a dual-function regulatory RNA involved in quorum-sensing processes and regulation of virulence factor expression. We also demonstrate that altering the natural NAD modification ratio of RNAIII leads to a decrease in exotoxin production, thereby modulating the bacterium’s virulence. Our work unveils a new layer of regulation of RNAIII and the agr system that might be linked to the redox state of the NAD molecule in the cell.

scholarly journals Targeting Methicillin-Resistant Staphylococcus aureus with Short Salt-Resistant Synthetic Peptides

2014 ◽  
Vol 58 (7) ◽  
pp. 4113-4122 ◽  
Author(s):  
Mohamed F. Mohamed ◽  
Maha I. Hamed ◽  
Alyssa Panitch ◽  
Mohamed N. Seleem
Keyword(s):  
Staphylococcus Aureus ◽  
Synthetic Peptides ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Net Charge ◽  
Methicillin Resistant ◽  
Content Type ◽  
C Terminus ◽  
Conventional Antibiotics

ABSTRACTThe seriousness of microbial resistance combined with the lack of new antimicrobials has increased interest in the development of antimicrobial peptides (AMPs) as novel therapeutics. In this study, we evaluated the antimicrobial activities of two short synthetic peptides, namely, RRIKA and RR. These peptides exhibited potent antimicrobial activity againstStaphylococcus aureus, and their antimicrobial effects were significantly enhanced by addition of three amino acids in the C terminus, which consequently increased the amphipathicity, hydrophobicity, and net charge. Moreover, RRIKA and RR demonstrated a significant and rapid bactericidal effect against clinical and drug-resistantStaphylococcusisolates, including methicillin-resistantStaphylococcus aureus(MRSA), vancomycin-intermediateS. aureus(VISA), vancomycin-resistantS. aureus(VRSA), linezolid-resistantS. aureus, and methicillin-resistantStaphylococcus epidermidis. In contrast to many natural AMPs, RRIKA and RR retained their activity in the presence of physiological concentrations of NaCl and MgCl2. Both RRIKA and RR enhanced the killing of lysostaphin more than 1,000-fold and eradicated MRSA and VRSA isolates within 20 min. Furthermore, the peptides presented were superior in reducing adherent biofilms ofS. aureusandS. epidermidiscompared to results with conventional antibiotics. Our findings indicate that the staphylocidal effects of our peptides were through permeabilization of the bacterial membrane, leading to leakage of cytoplasmic contents and cell death. Furthermore, peptides were not toxic to HeLa cells at 4- to 8-fold their antimicrobial concentrations. The potent and salt-insensitive antimicrobial activities of these peptides present an attractive therapeutic candidate for treatment of multidrug-resistantS. aureusinfections.

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