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1.
J Infect Dis ; 210(6): 973-81, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-24803533

ABSTRACT

BACKGROUND: Staphylococcal enterotoxin B (SEB), a potential biological warfare agent, is a potent superantigen that contributes to the virulence of methicillin-resistant Staphylococcus aureus (MRSA), which is a major health threat in the United States. Efforts to develop toxin-neutralizing antibodies as adjunctive therapies are justified, given the high mortality and frequent failure of therapy despite available antibiotics. METHODS: Murine SEB-specific mAb 20B1 was humanized, and treatment benefits of Hu-1.6/1.1 and Hu-1.4/1.1 variants were investigated in mice in an SEB intoxication model, as well as in sepsis and deep-tissue infection models. RESULTS: Hu-1.6/1.1 and Hu-1.4/1.1 protected mice against SEB-induced lethal shock. Hu-1.6/1.1 also enhanced survival of mice that developed fatal sepsis after challenge with a SEB-producing MRSA strain. Combined treatment of Hu-1.6/1.1 with vancomycin further increased survival and altered cytokine responses, compared with monotherapy with either monoclonal antibody or vancomycin alone. Efficacy was also demonstrated in the deep-tissue infection model, where Hu-1.4/1.1 bound to SEB in vivo and decreased abscess formation, as well as proinflammatory cytokine levels. CONCLUSIONS: SEB-neutralizing mAb 20B1 was successfully humanized. The mAb affects outcome by modulating the proinflammatory host response in both the sepsis and the intoxication models, which justifies further development.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Enterotoxins/immunology , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections/prevention & control , Vancomycin/therapeutic use , Abscess/immunology , Abscess/prevention & control , Animals , Anti-Bacterial Agents/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/immunology , Binding Sites, Antibody/immunology , Cytokines/blood , Enterotoxins/genetics , Methicillin-Resistant Staphylococcus aureus/immunology , Mice , Mice, Inbred BALB C , Staphylococcal Infections/immunology , Vancomycin/administration & dosage
2.
J Infect Dis ; 208(12): 2058-66, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-23922375

ABSTRACT

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has become a major health threat in the United States. Staphylococcal enterotoxin B (SEB) is a potent superantigen that contributes to its virulence. High mortality and frequent failure of therapy despite available antibiotics have stimulated research efforts to develop adjunctive therapies. METHODS: Treatment benefits of SEB-specific monoclonal antibody (mAb) 20B1 were investigated in mice in sepsis, superficial skin, and deep-tissue infection models. RESULTS: Mice challenged with a SEB-producing MRSA strain developed fatal sepsis, extensive tissue skin infection, and abscess-forming deep-seeded thigh muscle infection. Animals preimmunized against SEB or treated passively with mAb 20B1 exhibited enhanced survival in the sepsis model, whereas decrease of bacterial burden was observed in the superficial skin and deep-tissue models. mAb 20B1 bound to SEB in the infected tissue and decreased abscess formation and proinflammatory cytokine levels, lymphocyte proliferation, and neutrophil recruitment. CONCLUSIONS: mAb 20B1, an SEB-neutralizing mAb, is effective against MRSA infection. mAb 20B1 protects against lethal sepsis and reduces skin tissue invasion and deep-abscess formation. The mAb penetrates well into the abscess and binds to SEB. It affects the outcome of S. aureus infection by modulating the host's proinflammatory immune response.


Subject(s)
Antibodies, Monoclonal/pharmacology , Enterotoxins/immunology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/immunology , Abscess/microbiology , Abscess/pathology , Animals , Antibodies, Monoclonal/immunology , Enterotoxins/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Interleukins/blood , Interleukins/immunology , Mice , Mice, Inbred BALB C , Staphylococcal Infections/microbiology , Staphylococcal Infections/pathology , Staphylococcal Skin Infections , Staphylococcal Vaccines/immunology , Staphylococcus aureus/immunology , Superantigens/immunology , Superantigens/metabolism , Survival Analysis , T-Lymphocytes/immunology , Thigh/microbiology , Thigh/pathology , Virulence
3.
Peptides ; 27(7): 1877-85, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16574278

ABSTRACT

Beta-secretase 1 (BACE1) is an aspartic protease believed to play a critical role in Alzheimer's disease. Inhibitors of this enzyme have been designed by incorporating the non-cleavable hydroxyethylene and statine isosteres into peptides corresponding to BACE1 substrate sequences. We sought to develop new methods to quickly characterize and optimize inhibitors based on the statine core. Minimal sequence requirements for binding were first established using both crystallography and peptide spot synthesis. These shortened peptide inhibitors were then optimized by using spot synthesis to perform iterative cycles of substitution and deletion. The present study resulted in the identification of novel "bis-statine" inhibitors shown by crystallography to have a unique binding mode. Our results demonstrate the application of peptide spot synthesis as an effective method for enhancing peptidomimetic drug discovery.


Subject(s)
Amino Acids/chemistry , Biochemistry/methods , Endopeptidases/chemistry , Peptides/chemistry , Protease Inhibitors/pharmacology , Amino Acid Sequence , Amyloid Precursor Protein Secretases , Animals , Biotinylation , CHO Cells , Cricetinae , Crystallization , Crystallography , Models, Molecular , Molecular Sequence Data , Protein Conformation
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