Adam Belley

Adam Belley
Allecra Therapeutics · Microbiology

About

55
Publications
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1,320
Citations

Publications

Publications (55)
Article
Full-text available
Background Superior treatment outcomes were observed with the β-lactam/β-lactamase inhibitor combination of cefepime-enmetazobactam (FPE) compared to piperacillin-tazobactam (PTZ) in the primary efficacy population (m-MITT) of the ALLIUM phase 3 study of adult patients with cUTI/AP. We present here the outcomes in the microbiologically evaluable (M...
Article
Use of carbapenem antibiotics to treat infections caused by Enterobacterales expressing increasingly aggressive extended-spectrum β-lactamases (ESBL) has contributed to the emergence of carbapenem resistance. Enmetazobactam is a novel ESBL inhibitor being developed in combination with cefepime as a carbapenem-sparing option for infections caused by...
Article
Objectives : This study aimed to investigate third-generation cephalosporin (3GC) resistance determinants [extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases and OXA-type β-lactamases] in contemporary clinical Enterobacterales isolates and to determine the in vitro activity of β-lactams and β-lactam/β-lactamase inhibitor combinations, includ...
Article
Full-text available
Background There is a critical need for carbapenem-sparing therapies for infections caused by extended spectrum β-lactamase (ESBL)-producing Enterobacterales. Enmetazobactam is a novel ESBL inhibitor combined with the cephalosporin cefepime. Treatment outcomes of cefepime-enmetazobactam (FPE) versus piperacillin-tazobactam (PTZ) were assessed in su...
Article
Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae are classified as critical priority pathogens, with extended-spectrum β-lactamases (ESBLs) as principal resistance determinants. Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empiric treatment of serious Gram-negative infections...
Article
Klebsiella pneumoniae that produce extended spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being d...
Article
Third-generation cephalosporin resistance amongst Enterobacteriaceae , mediated by the spread of extended-spectrum β-lactamases (ESBLs), is a very serious medical concern with limited therapeutic options. Enmetazobactam (formerly AAI101) is a novel penicillanic sulfone β-lactamase inhibitor active against a wide range of ESBLs. The combination of e...
Article
Clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm although its safety and efficacy in treating clinical VRE...
Article
There are limited therapeutic options to treat infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The lipoglycopeptide oritavancin exhibits in vitro activity against this pathogen although its utility against infections caused by VREfm has not been established clinically. In this study, the pharmacodynamic activity of free-drug...
Article
The propensity of oritavancin to select for stably elevated oritavancin minimum inhibitory concentrations (MICs) was studied by serial passaging of strains in broth containing oritavancin for 20 days. Seven clinical strains of Enterococcus faecalis and E. faecium were studied; they included vancomycin-susceptible and both VanA and VanB vancomycin-r...
Article
Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study...
Article
Full-text available
Methicillin-resistant S. aureus (MRSA) infections constitute a threat to the public health due to their prevalence and associated mortality and morbidity. Several agents have been recently approved to treat MRSA skin infections including lipoglycopeptides (dalbavancin, oritavancin, and telavancin), ceftaroline, and tedizolid. This study compared th...
Article
Antibacterial agents that kill non-dividing bacteria may be of utility in treating persistent infections. Oritavancin and dalbavancin are bactericidal lipoglycopeptides approved for acute bacterial skin and skin structure infections in adults caused by susceptible gram-positive pathogens. Using time-kill methodology, we demonstrate that oritavancin...
Patent
Full-text available
The present invention is directed to a disk diffusion assay for determining susceptibility of bacteria to a glycopeptide antibiotic. The assay includes improvements over conventional assays due to the inclusion of polysorbate 80 and Span 80 in the antibacterial solution used to impregnate paper disks used in the assay.
Article
The scourge of resistance to antibacterial agents is a global problem of increasing severity. A recent review by Boucher and colleagues [33] summarized the alarming viewpoint of the Infectious Diseases Society of America (IDSA) that a stagnated development pipeline combined with continuing evolution of resistance, including emergence of pan-resista...
Article
The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a singl...
Data
Genetic control of early spleen bacillary counts of BCG Russia and BCG Pasteur. Linkage analysis of splenic bacterial counts at the week 1 time point was performed with an adjustment for strain genetic background and gender. A single locus on chromosome 1 was identified in response to early BCG Russia infection (A). Loci linked to splenic BCG Paste...
Data
Linkage analysis of late pulmonary counts independent of the genetic background. QTL analysis was performed using pulmonary counts of BCG Russia and BCG Pasteur at the week 6 time point. Loci controlling pulmonary bacterial numbers were identified on chromosome 11 for BCG Russia (A) and chromosome 8 for BCG Pasteur (B). Chromosomal positions are gi...
Data
Full-text available
Details of estimation, bootstrap and testing. (0.05 MB PDF)
Data
Linkage analysis of early splenic counts independent of the genetic background. Bacillary counts of BCG Russia and BCG Pasteur in the spleen of RC mice at the week 1 time point were used for QTL analysis. AA and BB genotype groups were analyzed without taking into account the gender or genetic background of the RC mice. Significant evidence for lin...
Data
Linkage analysis of late splenic counts independent of the genetic background. Bacterial numbers of BCG Russia and BCG Pasteur in the spleen of RC mice at the week 6 time point were used for linkage analysis. Significant linkages were detected on chromosomes 1 and 19 for BCG Russia (A) whereas no significant evidence for linkage was detected for BC...
Data
Genetic control of late spleen bacillary counts following infection of the RC strains with BCG Russia. Background- and gender-adjusted QTL analysis was performed using spleen counts of BCG Russia at the 6-week endpoint. A locus on chromosome 1 had a major effect on the bacterial numbers of BCG Russia. Additional loci were detected on chromosomes 6,...
Article
Full-text available
The host response to mycobacterial infection depends on host and pathogen genetic factors. Recent studies in human populations suggest a strain specific genetic control of tuberculosis. To test for mycobacterial-strain specific genetic control of susceptibility to infection under highly controlled experimental conditions, we performed a comparative...
Article
Oritavancin is an investigational lipoglycopeptide in clinical development for the treatment of acute bacterial skin and skin structure infections. In this study, we demonstrate that oritavancin causes bacterial membrane depolarization and permeabilization leading to cell death of Gram-positive pathogens and that these effects are attributable to t...
Article
Biophysical methods to study the binding of oritavancin, a lipoglycopeptide, to serum protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed oritavancin binding to serum from mouse, rat, dog, and human by a microbiological growth-based method under conditions that allow near-quantitative drug recovery. Protein bindin...
Article
The increasing incidence of antibiotic resistance in human pathogens is of significant concern. Resistance to the widely-used and highly effective glycopeptide antibacterial agent vancomycin, which has been in clinical use for over half a century, has emerged in staphylococci and enterococci. This has spurred the development of newer glycopeptide a...
Article
Oritavancin, a lipoglycopeptide, possesses bactericidal activity against Gram-positive bacteria including vancomycin-resistant Staphylococcus aureus and enterococci. To understand the time dependence of oritavancin activity, we have undertaken time-kill experiments against isolates of S. aureus, Enterococcus faecalis and Enterococcus faecium, inclu...
Article
Slow-growing bacteria and biofilms are notoriously tolerant to antibiotics. Oritavancin is a lipoglycopeptide with multiple mechanisms of action that contribute to its bactericidal action against exponentially growing gram-positive pathogens, including the inhibition of cell wall synthesis and perturbation of membrane barrier function. We sought to...
Article
Full-text available
The ultrastructural effects of the lipoglycopeptide oritavancin on methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) were examined by transmission electron microscopy. Oritavancin but not vancomycin induced aberrant septum formation and loss of staining of nascent septal cross walls in MRSA. Septal disto...
Conference Paper
Background: S. epidermidis (SE) forms biofilms that are notoriously tolerant to antimicrobial agents and that complicate infections of chronic wounds and indwelling medical devices. In this study, the efficacy of oritavancin (ORI), vancomycin (VAN), linezolid (LIN) and rifabutin (RFB) was determined against in vitro biofilms derived from SE clinica...
Conference Paper
Background: ORI is a lipoglycopeptide with bactericidal activity against VAN-intermediate SA (VISA) and VAN-resistant SA (VRSA). We assessed synergy in vitro between combinations of ORI + LIN against VISA isolates and ORI + NAF against the 8 available VRSA isolates from the Network on Antimicrobial Resistance in S. aureus (NARSA). Methods: Synergy...
Conference Paper
Background: Oritavancin (ORI), a synthetic derivative of the glycopeptide antibiotic chloroeremomycin (CEM), is in clinical development for treatment of serious gram-positive infections. Because ORI binds avidly to labware surfaces and is active against in vitro biofilms, we studied whether it could prevent biofilm formation (BF) by S. epidermidis,...
Article
Oritavancin is a semisynthetic lipoglycopeptide in clinical development for serious gram-positive infections. This study describes the synergistic activity of oritavancin in combination with gentamicin, linezolid, moxifloxacin, or rifampin in time-kill studies against methicillin-susceptible, vancomycin-intermediate, and vancomycin-resistant Staphy...
Article
Oritavancin, a semisynthetic lipoglycopeptide with activity against gram-positive bacteria, has multiple mechanisms of action, including the inhibition of cell wall synthesis and the perturbation of the membrane potential. Approved guidelines for broth microdilution MIC assays with dalbavancin, another lipoglycopeptide, require inclusion of 0.002%...
Article
Full-text available
Bacteriophages have evolved specific mechanisms that redirect bacterial metabolic pathways to the bacteriophage reproduction cycle. In this study, we characterized the bactericidal mechanism of two polypeptides from bacteriophages Twort and G1 that target the DNA sliding clamp of Staphylococcus aureus. The DNA sliding clamp, which tethers DNA polym...
Article
Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduc...
Article
The preparation and biological evaluation of 5-substituted-6-hydroxy-2-(anilino)pyrimidinones as a new class of DNA polymerase IIIC inhibitors, required for the replication of chromosomal DNA in Gram-positive bacteria, are described. These new dGTP competitive inhibitors displayed good levels of in vitro inhibition and antibacterial activity agains...
Article
Full-text available
BCG vaccines are a family of closely related daughter strains of an attenuated isolate of Mycobacterium bovis derived by in vitro passage from 1908 to 1921. During subsequent laboratory propagation of the vaccine strain until its lyophilization in 1961, BCG Pasteur underwent at least seven further genomic mutations. The impact of these mutations on...
Article
Full-text available
The intestinal protozoan parasite Entamoeba histolytica remains a significant cause of morbidity and mortality worldwide. However, almost nothing is known about the molecules secreted by the parasite that modulate host immune responses or epithelial barrier function in the colon. Herein, we describe the isolation and characterization of a cyclooxyg...
Article
Mucins form an integral part of innate host defenses against intestinal pathogens and irritants. However, the mechanisms whereby mucin secretion is regulated during inflammation are poorly understood. Because prostaglandin E(2) (PGE(2)) is prominent during intestinal inflammation, we investigated its receptor-signaling pathway coupled to mucin exoc...
Article
Intestinal mucins are key components of the first line of host defense against intestinal pathogens. These large glycoconjugates secreted by specialized exocrine goblet cells form viscous gels that trap microorganisms and irritants and limit their diffusion to the intestinal epithelium. Moreover, they allow for colonization by indigenous bacterial...
Article
Mucins secreted from the gastrointestinal epithelium from the basis of the adherent mucus layer which is the host's first line of defense against invasion by Entamoeba histolytica. Galactose and N-acetyl-D-galactosamine residues of mucins specifically inhibit binding of the amebic 170 kDa heavy subunit Gal-lectin to target cells, an absolute prereq...
Article
Colonic mucins secreted by goblet cells protect the colon by preventing the attachment of enteric pathogens to the epithelium. Entamoeba histolytica overcomes this protective barrier and causes ulcerations, allowing the parasite to disseminate to the liver and form abscesses. An in vitro model is used to study the interaction between E. histolytica...
Article
At present it is unclear whether nonsteroidal antiinflammatory drugs (NSAIDs) can inhibit cyclooxygenase (COX) gene expression. In some cells that express COX-2, NSAIDs can inhibit enzymatic activity and gene expression. In this study we evaluated the effect of several NSAIDs on COX-1 and COX-2 mRNA, protein expression and PGE2 production in PMA-di...
Article
In this review, Adam Belley and Kris Chadee discuss eicosanoid production by various parasites and propose roles they may play in pathogenesis and immunomodulation. The commonality between parasites is prostaglandin production and, therefore, special attention is given to the cyclooxygenase pathway, highlighting the enzymes and functions of prostag...
Article
In this review, Adam Belley and Kris Chadee discuss eicosanoid production by various parasites and propose roles they may play in pathogenesis and immunomodulation. The commonality between parasites is prostaglandin production and, therefore, special attention is given to the cyclooxygenase pathway, highlighting the enzymes and functions of prostag...
Article
The enteric protozoan parasite Entamoeba histolytica is the etiologic agent of the disease amebiasis which is characterized by colitis or hepatic lesions. Amebae colonize the colon by binding to mucous glycoproteins (mucins). Secretory mucins provide the gel nature to mucus and are a vital component of epithelial barrier function. Mucins prevent co...

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