A5006271408- Antibiotic Resistance in Bacteria
- Antibiotics Pharmacokinetics and Efficacy
- Antibiotic Use and Resistance
- Bacterial Genetics and Biotechnology
- Antimicrobial Resistance in Staphylococcus
- Pneumonia and Respiratory Infections
- Bacterial biofilms and quorum sensing
- Pharmaceutical and Antibiotic Environmental Impacts
- Vibrio bacteria research studies
- Tuberculosis Research and Epidemiology
- Cancer therapeutics and mechanisms
- Microbial Natural Products and Biosynthesis
- Berberine and alkaloids research
- Pneumocystis jirovecii pneumonia detection and treatment
- Pancreatic function and diabetes
- Streptococcal Infections and Treatments
- Urinary Tract Infections Management
- Glycosylation and Glycoproteins Research
- Escherichia coli research studies
- Mycobacterium research and diagnosis
- Developmental Biology and Gene Regulation
- Machine Learning in Bioinformatics
- Phenothiazines and Benzothiazines Synthesis and Activities
- Protein purification and stability
- Adenosine and Purinergic Signaling
Innoviva (United States)
2023-2025
Entasis Therapeutics (United States)
2015-2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2023-2024
AstraZeneca (United States)
2015
Pfizer (United States)
2008-2014
North Carolina State University
2014
AstraZeneca (United Kingdom)
2014
Monash University
2008-2012
Pearl River Community College
2012
Centre National de la Recherche Scientifique
1998-2003
Sulbactam is a class A β-lactamase inhibitor with intrinsic whole-cell activity against certain bacterial species, including Acinetobacter baumannii. The clinical use of sulbactam for A. baumannii infections interest due to increasing multidrug resistance in this pathogen. However, the molecular drivers its antibacterial and determinants have yet be precisely defined. Here we show that activities vary widely across contemporary isolates are mediated through inhibition penicillin-binding...
CsrS/CsrR is a 2-component system in Streptococcus pyogenes that negatively regulates hyaluronic capsule and several exotoxins. To detect spontaneous mutations csrRS mucoid large colony variants of M1 strain MGAS166 were isolated from experimental murine skin infections. By use complementation with csrRS+ plasmid, relevant also detected 7 12 human clinical isolates. The presence mutants mouse infection was associated larger, more necrotic lesions. Most changes CsrR resulted single amino acid...
The Centers for Disease Control and the World Health Organization have issued a list of priority pathogens which there are dwindling therapeutic options, including antibiotic-resistant Neisseria gonorrheae, novel oral agents urgently needed. Zoliflodacin, first in new class antibacterial called spiropyrimidinetriones, is being developed treatment gonorrhea. It has unique mode inhibition against bacterial type II topoisomerases with binding sites gyrase that distinct from those...
The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited avoid many the preexisting antibiotic mechanisms are rapidly disseminating strains. discovery small-molecule inhibitors LpxC, enzyme responsible for first committed step biosynthesis lipid A, represents a clinically unprecedented strategy specifically act against organisms such as Pseudomonas aeruginosa members...
A high-throughput phenotypic screen based on a Citrobacter freundii AmpC reporter expressed in Escherichia coli was executed to discover novel inhibitors of bacterial cell wall synthesis, an attractive, well-validated target for antibiotic intervention. Here we describe the discovery and characterization sulfonyl piperazine pyrazole compounds, each with mechanisms action. E. mutants resistant these compounds display no cross-resistance antibiotics other classes. Resistance maps LpxH, which...
Sulbactam-durlobactam is a β-lactam-β-lactamase inhibitor combination designed to treat serious Acinetobacter baumannii -calcoaceticus complex (ABC) infections, including carbapenem-non-susceptible and multidrug-resistant (MDR) isolates. The current study characterized the in vitro activity of sulbactam-durlobactam against collection 5,032 ABC clinical isolates collected 33 countries across Asia/South Pacific region, Europe, Latin America, Middle East, North America from 2016 2021.
OmpAAb is a conserved, abundantly expressed outer membrane porin in Acinetobacter baumannii whose presumed role antibiotic permeation has not been clearly demonstrated. In this report, we use titratable heterologous expression system to express isolation and demonstrate selective passage of small molecule antibiotics through OmpAAb. ETX2514, recently discovered broad-spectrum β-lactamase inhibitor, combination with sulbactam, currently clinical testing for the treatment drug-resistant A....
In Gram-negative bacteria, lipoproteins are transported to the outer membrane by Lol system. this process, released from inner ABC transporter LolCDE and passed LolA, a diffusible periplasmic molecular chaperone. Lipoproteins then transferred receptor protein, LolB, for insertion in membrane. Here we describe discovery characterization of novel pyridineimidazole compounds that inhibit process. Escherichia coli mutants resistant pyridineimidazoles show no cross-resistance other classes...
The objective of this study was to investigate the risk attenuated efficacy due adaptive resistance for siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined cation-adjusted Mueller-Hinton broth (MHB) and Chelex-treated, dialyzed MHB (CDMHB). Spontaneous assessed at 2× 16× MIC resulting mutants sequenced. Efficacy evaluated neutropenic mouse thigh model 3.13 400 mg/kg body weight every 3 h 24...
Significant challenges are present in antibiotic drug discovery and development. One of these is the number efficient approaches Gram-negative bacteria have developed to avoid intracellular accumulation drugs other cell-toxic species. In order better understand processes correlate vitro enzyme inhibition whole cell activity, a assay evaluate key factor, drug, urgently needed. Here, we describe unique liquid chromatography (LC)-mass spectrometry (MS) approach measure amount cellular uptake...
Acinetobacter baumannii-calcoaceticus complex (ABC) organisms cause severe infections that are difficult to treat due preexisting antibiotic resistance. Sulbactam-durlobactam (formerly sulbactam-ETX2514) (SUL-DUR) is a β-lactam-β-lactamase inhibitor combination designed serious caused by ABC organisms, including multidrug-resistant (MDR) strains. The in vitro antibacterial activities of SUL-DUR and comparator agents were determined broth microdilution against 1,722 clinical isolates...
Abstract Objectives To evaluate the activity of novel broad-spectrum serine β-lactamase inhibitor durlobactam (ETX2514) combined with sulbactam against global isolates carbapenem-resistant Acinetobacter baumannii defined carbapenem resistance mechanisms compared reference antimicrobials known spp. Methods The susceptibility 246 non-duplicate A. to sulbactam/durlobactam, amikacin, colistin, imipenem/sulbactam/durlobactam, imipenem, meropenem, minocycline and was tested using broth...
Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward β-lactam antibiotics. The hydrolytic enzymes called β-lactamases responsible for a large proportion of the phenotype. β-Lactamase inhibitors (BLIs) can be administered in combination with antibiotics negate action β-lactamases, thereby restoring activity β-lactam. Newly developed BLIs offer some advantage over older terms enzymatic spectrum but limited...
Abstract Sulbactam-durlobactam is a pathogen-targeted β-lactam/β-lactamase inhibitor combination in late-stage development for the treatment of Acinetobacter infections, including those caused by multidrug-resistant strains. Durlobactam member diazabicyclooctane class β-lactamase inhibitors with broad-spectrum serine activity. Sulbactam first-generation, narrow-spectrum that also has intrinsic antibacterial activity against spp. due to its ability inhibit penicillin-binding proteins 1 and 3....
QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic is an unusual barbituric acid derivative whose activity resides the (-)-enantiomer. had against broad spectrum of pathogenic, antibiotic-resistant bacteria, nontoxic to eukaryotic cells, showed oral efficacy murine infection model, all before any medicinal chemistry optimization. Biochemical genetic characterization that targets beta...
Acinetobacter baumannii AYE does not produce acinetobactin but grows under iron limitation. Accordingly, analyses of iron-restricted culture supernatants resulted in the isolation two fractions, which contained only hydroxamates and showed siderophore activity. Structural identified baumannoferrin A B, differ by a double bond. These siderophores are composed citrate, 1,3-diaminopropane, 2,4-diaminobutyrate, decenoic acid, α-ketoglutarate. Analysis genome presence 12-gene cluster coding for...
ETX2514 is a non-β-lactam serine β-lactamase inhibitor in clinical development that has greater potency and broader spectrum of inhibition than the related diazabicyclooctanone avibactam. Despite opening its cyclic urea ring upon acylation, avibactam can recyclize dissociate intact from certain β-lactamases. We investigated reversibility acylation 10 β-lactamases representing Ambler classes A, C, D. Dissociation rate constants varied widely between enzymes were lowest for class For most...