A5077367742- Bacterial biofilms and quorum sensing
- Antibiotic Resistance in Bacteria
- Immune Response and Inflammation
- Bacteriophages and microbial interactions
- Pneumonia and Respiratory Infections
- Vibrio bacteria research studies
- Bacterial Genetics and Biotechnology
- Monoclonal and Polyclonal Antibodies Research
- Bacterial Infections and Vaccines
- Ocular Infections and Treatments
- Inhalation and Respiratory Drug Delivery
- Nosocomial Infections in ICU
- Glycosylation and Glycoproteins Research
- Antimicrobial Peptides and Activities
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Carbohydrate Chemistry and Synthesis
- Probiotics and Fermented Foods
- Escherichia coli research studies
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Cystic Fibrosis Research Advances
- Clostridium difficile and Clostridium perfringens research
- Cytokine Signaling Pathways and Interactions
- Antimicrobial Resistance in Staphylococcus
- RNA Interference and Gene Delivery
- NF-κB Signaling Pathways
AstraZeneca (United States)
2019-2025
University of Virginia Health System
2007-2023
Serimmune (United States)
2018
University of Virginia
2004-2015
Vanderbilt University
2009-2014
University of Georgia
2013
Vanderbilt University Medical Center
2009-2010
Duquesne University
2002
Zero to Three
2002
A new antibody platform combining anti-Psl and anti-PcrV activities provides enhanced protection acts synergistically with antibiotics against Pseudomonas aeruginosa .
Pseudomonas aeruginosa is a leading cause of hospital-associated infections in the seriously ill, and primary agent chronic lung cystic fibrosis patients. A major obstacle to effective control P. its intrinsic resistance most antibiotic classes, which results from chromosomally encoded drug-efflux systems multiple acquired mechanisms selected by years aggressive therapy. These factors demand new strategies drugs prevent treat infections. Herein, we describe monoclonal antibody (mAb)...
S. aureus α toxin promotes opportunistic co-infection, which can be neutralized with a pathogen-specific antibody.
ABSTRACT Pseudomonas aeruginosa is a major cause of hospital-acquired infections, particularly in mechanically ventilated patients, and it the leading death cystic fibrosis patients. A key virulence factor associated with disease severity P. type III secretion system (T3SS), which injects bacterial toxins directly into cytoplasm host cells. The PcrV protein, located at tip T3SS injectisome complex, required for function well-validated target animal models immunoprophylactic strategies...
MEDI3902 is a bivalent, bispecific human immunoglobulin G1κ monoclonal antibody that binds to both the Pseudomonas aeruginosa PcrV protein involved in host cell cytotoxicity and Psl exopolysaccharide P. colonization tissue adherence. being developed for prevention of nosocomial pneumonia high-risk patients.This phase 1 dose-escalation study (NCT02255760) evaluated safety, pharmacokinetics, antidrug (ADA) responses ex vivo anticytotoxicity opsonophagocytic killing activities after single...
Abstract Emerging multidrug-resistant bacteria are a challenge for modern medicine, but how these pathogens so successful is not fully understood. Robust antibacterial vaccines have prevented and reduced resistance suggesting pivotal role immunity in deterring antibiotic resistance. Here, we show the increased prevalence of Klebsiella pneumoniae lipopolysaccharide O2 serotype strains all major drug groups correlating with paucity anti-O2 antibodies human B cell repertoires. We identify...
Abstract Background Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) preventing PA nosocomial was assessed PA-colonised mechanically ventilated subjects. Methods EVADE (NCT02696902) a phase 2, randomised, parallel-group, double-blind, placebo-controlled study Europe, Turkey, Israel, and USA. Subjects ≥ 18 years old, ventilated, tracheally...
Pseudomonas aeruginosa is a major cause of severe infections that lead to bacteremia and high patient mortality. P. has evolved numerous evasion subversion mechanisms work in concert overcome immune recognition effector functions hospitalized immunosuppressed individuals. Here, we have used multilaser spinning-disk intravital microscopy monitor the blood-borne stage murine bacteremic model infection. adhered avidly lung vasculature, where patrolling neutrophils other cells were virtually...
The impact of broad-spectrum antibiotics on antimicrobial resistance and disruption the beneficial microbiome compels urgent investigation bacteria-specific approaches such as antibody-based strategies. Among these, DNA-delivered monoclonal antibodies (DMAbs), produced by muscle cells in vivo, potentially allow prevention or treatment bacterial infections circumventing some hurdles protein IgG delivery. Here, we optimize consisting two potent human clones, including a non-natural bispecific...
Bispecific antibody MEDI3902, targeting the Pseudomonas aeruginosa type 3 secretion system (PcrV) and Psl exopolysaccharide, is currently in phase 2b development for prevention of nosocomial pneumonia patients undergoing mechanical ventilation. We surveyed a diverse collection isolates to study MEDI3902 epitope conservation protective activity. P. clinical (n = 913) were collected from geographic locations during 2003–2014. conducted whole-genome sequencing; performed PcrV expression...
Neutrophils abandon infection control during wound repair.
The exopolysaccharide Psl contributes to biofilm structure and antibiotic tolerance may play a role in the failure eradicate Pseudomonas aeruginosa from cystic fibrosis (CF) airways. study objective was determine whether there were any differences P. isolates that successfully eradicated compared those persisted, despite inhaled tobramycin treatment, children with CF. Initial collected CF undergoing eradication grown as biofilms labeled 3 anti-Psl monoclonal antibodies (Cam003/Psl0096,...
Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care–associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan improved survival reduced bacterial burden mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus aureus , vancomycin-resistant Enterococcus faecalis extended-spectrum beta-lactamase–expressing...
Summary The structural similarity between the pilin glycan and O‐antigen of Pseudomonas aeruginosa 1244 suggested that they have a common metabolic origin. Mutants this organism lacking functional wbpM or wbpL genes synthesized no produced only non‐glycosylated pilin. Complementation with plasmids containing fully restored ability to produce both glycosylated Expression cosmid clone biosynthetic gene cluster from P. PA103 (LPS serotype O11) in O7) resulted production strain pili contained O7...
Surface-expressed bacterial polysaccharides are often immunodominant, protective antigens. However, these antigens chemically and serologically highly heterogeneous, conjugation to protein carriers is necessary enhance their immunogenicity. Here we show the efficacy of intranasal immunization mice with attenuated Salmonella enterica serovar Typhimurium expressing O antigen portion Pseudomonas aeruginosa lipopolysaccharide. P. an ideal model system because it can cause a myriad localized...
The Steroids for Corneal Ulcers Trial (SCUT) was a multicenter, international study of bacterial keratitis in which 101 Pseudomonas aeruginosa infections were treated. Twenty-two P. isolates collected had colony morphology characteristic loss-of-function mutation lasR, the gene encoding quorum-sensing master regulator. caused by these 22 strains associated with larger areas corneal opacification, worse vision, and lower rate vision recovery response to treatment than ulcers other isolates....
Abstract Background Clostridioides difficile infection (CDI) cause mild to severe diarrhea and can be life threatening. Because toxin B is a clinically validated target for CDI, we have generated an anti-toxin neutralizing monoclonal antibody (mAb) AZD5148. We previously demonstrated that AZD5148 administered at 10, 1 0.5 mg/kg prevents disease development in gnotobiotic piglet model, which recapitulates the clinical signs gross pathology observed human compared protective efficacy of with...
Pseudomonas aeruginosa is a leading cause of nosocomial pneumonia. We compared the efficacies oral and intraperitoneal (i.p.) vaccinations BALB/c mice with attenuated Salmonella enterica serovar Typhimurium SL3261 expressing P. serogroup O11 O antigen to protect against infection in an acute fatal pneumonia model. Oral i.p. vaccines elicited O11-specific serum immunoglobulin G (IgG) antibodies, but IgA was observed only after immunization. Challenge orally vaccinated strain (9882-80) at 6 12...
Acute lung inflammation is a potentially life-threatening complication of infections due to community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), worldwide emerging pathogen, which causes necrotizing pneumonia and acute respiratory distress syndrome (ARDS). MRSA virulence factors encompass immunotoxins termed superantigens that contribute inflammation. In this study, we demonstrate staphylococcal enterotoxin B (SEB)-induced attenuated by cell-penetrating peptide nuclear...
Abstract All Enterobacteriaceae express a polysaccharide known as enterobacterial common antigen (ECA), which is an attractive target for the development of universally acting immunotherapies. The first chemical synthesis ECA‐derived oligosaccharides such therapies described. A number synthetic challenges had to be addressed, including concise procedures unusual monosaccharides, selection appropriate orthogonal protecting groups, stereoselective glycosylation methods, timing introduction...
Pseudomonas aeruginosa is among the most formidable antibiotic-resistant pathogens and a leading cause of hospital-associated infections. With dwindling options for infections, new paradigm treatment disease resolution required. MEDI3902, bispecific antibody targeting P. type III secretion (T3S) protein PcrV Psl exopolysaccharide, was previously shown to mediate potent protective activity in murine infection models. current challenges associated with clinical development narrow-spectrum...