scholarly journals Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of SeriousStaphylococcus aureusDisease

mBio ◽  
2016 ◽  
Vol 7 (3) ◽  
Author(s):  
C. Tkaczyk ◽  
M. M. Hamilton ◽  
A. Sadowska ◽  
Y. Shi ◽  
C.S. Chang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Disease Severity ◽  
Virulence Factors ◽  
Bloodstream Infections ◽  
Multiple Infection ◽  
Alpha Toxin ◽  
Bacterial Killing ◽  
Fibrinogen Binding ◽  
Bacterial Agglutination

ABSTRACTStaphylococcus aureusproduces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT monoclonal antibody (MAb), MEDI4893*, has been shown to reduce disease severity in dermonecrosis and pneumonia infection models. However, interstrain diversity and the complex pathogenesis ofS. aureusbloodstream infections suggests that MEDI4893* alone may not provide adequate protection againstS. aureussepsis. Clumping factor A (ClfA), a fibrinogen binding protein, is an important virulence factor facilitatingS. aureusbloodstream infections. Herein, we report on the identification of a high-affinity anti-ClfA MAb, 11H10, that inhibits ClfA binding to fibrinogen, prevents bacterial agglutination in human plasma, and promotes opsonophagocytic bacterial killing (OPK). 11H10 prophylaxis reduced disease severity in a mouse bacteremia model and was dependent on Fc effector function and OPK. Additionally, prophylaxis with 11H10 in combination with MEDI4893* provided enhanced strain coverage in this model and increased survival compared to that obtained with the individual MAbs. The MAb combination also reduced disease severity in murine dermonecrosis and pneumonia models, with activity similar to that of MEDI4893* alone. These results indicate that an MAb combination targeting multiple virulence factors provides benefit over a single MAb neutralizing one virulence mechanism by providing improved efficacy, broader strain coverage, and protection against multiple infection pathologies.IMPORTANCEAlternative strategies to broad-spectrum antibiotics are required to combat the antibiotic resistance epidemic. Previous attempts at active or passive immunization againstStaphylococcus aureustargeting single antigens have failed in clinical trials despite positive preclinical data. To provide broad disease and isolate coverage, an effective immunization strategy likely must target multiple virulence mechanisms of the pathogen. Herein, we tested a multimechanistic MAb combination targeting alpha toxin (AT) and clumping factor A (ClfA) that neutralizes AT-mediated cytotoxicity, blocks fibrinogen binding by ClfA, prevents bacterial agglutination, targets the bacteria for opsonophagocytic killing, and provides broad isolate coverage in a lethal-bacteremia model. Although each MAb alone was effective in bacteremia against some individual isolates, the MAb combination provided improved protection against other isolates. These results illustrate the importance of targeting multiple virulence mechanisms and highlight the potential for an MAb combination targeting AT and ClfA to effectively preventS. aureusdisease.

scholarly journals Efficacy of a Multimechanistic Monoclonal Antibody Combination against Staphylococcus aureus Surgical Site Infections in Mice

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Roger V. Ortines ◽  
Yu Wang ◽  
Haiyun Liu ◽  
Dustin A. Dikeman ◽  
Bret L. Pinsker ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Mouse Models ◽  
Virulence Factors ◽  
Surgical Site Infections ◽  
Alpha Toxin ◽  
Content Type

ABSTRACT Surgical site infections (SSIs) are commonly caused by Staphylococcus aureus. We report that a combination of three monoclonal antibodies (MEDI6389) that neutralize S. aureus alpha-toxin, clumping factor A, and four leukocidins (LukSF, LukED, HlgAB, and HlgCB) plus vancomycin had enhanced efficacy compared with control antibody plus vancomycin in two mouse models of S. aureus SSI. Therefore, monoclonal antibody-based neutralization of multiple S. aureus virulence factors may provide an adjunctive perioperative approach to combat S. aureus SSIs.

scholarly journals Correction: Detection of Alpha-Toxin and Other Virulence Factors in Biofilms of Staphylococcus aureus on Polystyrene and a Human Epidermal Model

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0152544 ◽  
Author(s):  
P. M. den Reijer ◽  
E. M. Haisma ◽  
N. A. Lemmens-den Toom ◽  
J. Willemse ◽  
R. I. Koning ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Alpha Toxin

A human monoclonal antibody with the capacity to neutralize Staphylococcus aureus alpha-toxin

1994 ◽  
Vol 5 (1-2) ◽  
pp. 18-24 ◽  
Author(s):  
Nikolaus Heveker ◽  
Arne Hansen ◽  
Klaus-Dieter Hungerer ◽  
Rüdiger von Baehr ◽  
Ralf W. Glaser
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Human Monoclonal Antibody ◽  
Alpha Toxin

scholarly journals Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

2014 ◽  
Vol 59 (1) ◽  
pp. 299-309 ◽  
Author(s):  
Jamese J. Hilliard ◽  
Vivekananda Datta ◽  
Christine Tkaczyk ◽  
Melissa Hamilton ◽  
Agnieszka Sadowska ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Soft Tissue ◽  
Single Agent ◽  
Alpha Toxin ◽  
Tissue Necrosis ◽  
Content Type ◽  
Infection Models ◽  
Neutralizing Monoclonal Antibody ◽  
Treatment Window

ABSTRACTAlpha-toxin (AT) is a major virulence determinant inStaphylococcus aureusskin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), preventsS. aureusdisease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment ofS. aureusskin and soft tissue infections.

scholarly journals Staphylococcus aureus Alpha-Toxin Is Conserved among Diverse Hospital Respiratory Isolates Collected from a Global Surveillance Study and Is Neutralized by Monoclonal Antibody MEDI4893

2016 ◽  
Vol 60 (9) ◽  
pp. 5312-5321 ◽  
Author(s):  
David E. Tabor ◽  
Li Yu ◽  
Hoyin Mok ◽  
Christine Tkaczyk ◽  
Bret R. Sellman ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Vaccine Development ◽  
Geographic Location ◽  
The United States ◽  
Geographic Region ◽  
Alpha Toxin ◽  
Content Type ◽  
Gene Sequence Analysis ◽  
The Subject

ABSTRACTStaphylococcus aureusinfections lead to an array of illnesses ranging from mild skin infections to serious diseases, such endocarditis, osteomyelitis, and pneumonia. Alpha-toxin (Hla) is a pore-forming toxin, encoded by thehlagene, that is thought to play a key role inS. aureuspathogenesis. A monoclonal antibody targeting Hla, MEDI4893, is in clinical development for the prevention ofS. aureusventilator-associated pneumonia (VAP). The presence of thehlagene and Hla protein in 994 respiratory isolates collected from patients in 34 countries in Asia, Europe, the United States, Latin America, the Middle East, Africa, and Australia was determined. Hla levels were correlated with the geographic location, age of the subject, and length of stay in the hospital.hlagene sequence analysis was performed, and mutations were mapped to the Hla crystal structure.S. aureussupernatants containing Hla variants were tested for susceptibility or resistance to MEDI4893. Thehlagene was present and Hla was expressed in 99.0% and 83.2% of the isolates, respectively, regardless of geographic region, hospital locale, or age of the subject. More methicillin-susceptible than methicillin-resistant isolates expressed Hla (86.9% versus 78.8%;P= 0.0007), andS. aureusisolates from pediatric patients expressed the largest amounts of Hla. Fifty-seven different Hla subtypes were identified, and 91% of the isolates encoded an Hla subtype that was neutralized by MED4893. This study demonstrates that Hla is conserved in diverseS. aureusisolates from around the world and is an attractive target for prophylactic monoclonal antibody (MAb) or vaccine development.

scholarly journals 1557. Population Pharmacokinetics of Suvratoxumab (MEDI4893), an Extended Half-life Staphylococcus aureus Alpha Toxin-Neutralizing Human Monoclonal Antibody, in Healthy Adults and Patients on Mechanical Ventilation in Intensive Care Units

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S568-S569
Author(s):  
Vadryn Pierre ◽  
Bruno Francois ◽  
Martha Hernandez-Illas ◽  
Miguel Sánchez Garcia ◽  
Yuling Wu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Mechanical Ventilation ◽  
Healthy Volunteers ◽  
Population Pharmacokinetics ◽  
Half Life ◽  
Human Monoclonal Antibody ◽  
Healthy Adults ◽  
Alpha Toxin ◽  
Post Dose

Abstract Background Suvratoxumab (suvra), an extended half-life (~80 days), Staphylococcus aureus (SA) alpha toxin-neutralizing IgG monoclonal antibody, is under investigation for prevention of SA pneumonia in patients on mechanical ventilation (MV). We characterized the serum PK of suvra using population pharmacokinetics (popPK) in both healthy volunteers and MV patients and quantified the proportion of patients reaching the serum target of 211 μg/mL at 30 days post-dose. Methods The popPK analysis included 1,368 serum samples from two early phase studies (NCT02296320; EudraCT 2014-001097-34): (1) Phase 1 study in 26 healthy adults receiving single IV suvra doses ranging from 0.225g to 5g, with PK sampled up to 360 days; and (2) Phase 2 study in MV patients with PCR-confirmed SA colonization of lower respiratory tract receiving one suvra IV dose of 2g (n = 15) or 5g (n = 96), with PK sampled up to 100 days. Results A two-compartment linear model with weight-based scaling of the PK parameters adequately described the serum PK data (Figure 1). MV status, number of days on MV, and age impacted the PK of suvra. A moderate between-subject variability (<45% CV) was estimated for key PK parameters. An estimated two-fold increase in MV patients’ volume of distribution parameters compared with healthy volunteers explained the observed Cmax differences between the two groups (1145±369 μg/mL vs. 1783±396 μg/mL) (Figures 2 and 3). Although age, MV status and days on MV post-dose appeared to be associated with higher systemic clearance (CL) in the model, this estimate could be biased due to limited PK data available for only one half-life (~90 days) of the drug in MV patients (Figure 2). More patients achieved suvra levels above the PK target following the 5 g (73.5%; 50/68) vs. 2 g dose (7.6%; 1/13) at 30 days post-dose. Conclusion MV status, post-dose duration on MV, body weight, and age were identified as statistically significant covariates influencing the PK of suvra. Serum PK and popPK analyses support the 5g dose for future studies with suvra in MV patients. Disclosures All authors: No reported disclosures.

scholarly journals The Increased Accumulation of Staphylococcus aureus Virulence Factors Is Maximized in a purR Mutant by the Increased Production of SarA and Decreased Production of Extracellular Proteases

2021 ◽  
Vol 89 (4) ◽  
Author(s):  
Duah Alkam ◽  
Piroon Jenjaroenpun ◽  
Aura M. Ramirez ◽  
Karen E. Beenken ◽  
Horace J. Spencer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Binding Proteins ◽  
Protease Production ◽  
Alpha Toxin ◽  
Extracellular Proteases ◽  
Content Type ◽  
Enhanced Production ◽  
Fibronectin Binding ◽  
The Impact

ABSTRACT Mutation of purR was previously shown to enhance the virulence of Staphylococcus aureus in a murine sepsis model, and this cannot be fully explained by increased expression of genes within the purine biosynthesis pathway. Rather, the increased production of specific S. aureus virulence factors, including alpha toxin and the fibronectin-binding proteins, was shown to play an important role. Mutation of purR was also shown previously to result in increased abundance of SarA. Here, we demonstrate by transposon sequencing that mutation of purR in the USA300 strain LAC increases fitness in a biofilm while mutation of sarA has the opposite effect. Therefore, we assessed the impact of sarA on reported purR-associated phenotypes by characterizing isogenic purR, sarA, and sarA/purR mutants. The results confirmed that mutation of purR results in increased abundance of alpha toxin, protein A, the fibronectin-binding proteins, and SarA, decreased production of extracellular proteases, an increased capacity to form a biofilm, and increased virulence in an osteomyelitis model. Mutation of sarA had the opposite effects on all of these phenotypes and, other than bacterial burdens in the bone, all of the phenotypes of sarA/purR mutants were comparable to those of sarA mutants. Limiting the production of extracellular proteases reversed all of the phenotypes of sarA mutants and most of those of sarA/purR mutants. We conclude that a critical component defining the virulence of a purR mutant is the enhanced production of SarA, which limits protease production to an extent that promotes the accumulation of critical S. aureus virulence factors.

scholarly journals Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Caleb A. Ford ◽  
Ian M. Hurford ◽  
James E. Cassat
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Tissue Injury ◽  
Therapeutic Targets ◽  
Multiple Infection ◽  
Human Pathogens ◽  
Host Immune Responses ◽  
Infection Models ◽  
Antimicrobial Treatments

Staphylococcus aureus is a Gram-positive bacterium capable of infecting nearly all host tissues, causing severe morbidity and mortality. Widespread antimicrobial resistance has emerged among S. aureus clinical isolates, which are now the most frequent causes of nosocomial infection among drug-resistant pathogens. S. aureus produces an array of virulence factors that enhance in vivo fitness by liberating nutrients from the host or evading host immune responses. Staphylococcal virulence factors have been identified as viable therapeutic targets for treatment, as they contribute to disease pathogenesis, tissue injury, and treatment failure. Antivirulence strategies, or treatments targeting virulence without direct toxicity to the inciting pathogen, show promise as an adjunctive therapy to traditional antimicrobials. This Mini Review examines recent research on S. aureus antivirulence strategies, with an emphasis on translational studies. While many different virulence factors have been investigated as therapeutic targets, this review focuses on strategies targeting three virulence categories: pore-forming toxins, immune evasion mechanisms, and the S. aureus quorum sensing system. These major areas of S. aureus antivirulence research demonstrate broad principles that may apply to other human pathogens. Finally, challenges of antivirulence research are outlined including the potential for resistance, the need to investigate multiple infection models, and the importance of studying antivirulence in conjunction with traditional antimicrobial treatments.

scholarly journals Assessment of an Anti-Alpha-Toxin Monoclonal Antibody for Prevention and Treatment of Staphylococcus aureus-Induced Pneumonia

2013 ◽  
Vol 58 (2) ◽  
pp. 1108-1117 ◽  
Author(s):  
L. Hua ◽  
J. J. Hilliard ◽  
Y. Shi ◽  
C. Tkaczyk ◽  
L. I. Cheng ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Immune Cell ◽  
Passive Immunization ◽  
Lavage Fluid ◽  
Alpha Toxin ◽  
Content Type ◽  
Promising Target ◽  
Insight Into ◽  
Inflammatory Tissue

ABSTRACTAlpha-toxin (AT) is a major virulence factor in the disease pathogenesis ofStaphylococcus aureus. We previously identified a monoclonal antibody (MAb) against AT that reduced disease severity in a mouse dermonecrosis model. Here, we evaluate the activity of an affinity-optimized variant, LC10, in a mouse model ofS. aureuspneumonia. Passive immunization with LC10 increased survival and reduced bacterial numbers in the lungs and kidneys of infected mice and showed protection against diverseS. aureusclinical isolates. The lungs ofS. aureus-infected mice exhibited bacterial pneumonia, including widespread inflammation, whereas the lungs of mice that received LC10 exhibited minimal inflammation and retained healthy architecture. Consistent with reduced immune cell infiltration, LC10-treated animals had significantly lower (P< 0.05) proinflammatory cytokine and chemokine levels in the bronchoalveolar lavage fluid than did those of the control animals. This reduction in inflammation and damage to the LC10-treated animals resulted in reduced vascular protein leakage and CO2levels in the blood. LC10 was also assessed for its therapeutic activity in combination with vancomycin or linezolid. Treatment with a combination of LC10 and vancomycin or linezolid resulted in a significant increase (P< 0.05) in survival relative to the monotherapies and was deemed additive to synergistic by isobologram analysis. Consistent with improved survival, the lungs of animals treated with antibiotic plus LC10 exhibited less inflammatory tissue damage than those that received monotherapy. These data provide insight into the mechanisms of protection provided by AT inhibition and support AT as a promising target for immunoprophylaxis or adjunctive therapy againstS. aureuspneumonia.

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