A5084193524- Antibiotic Resistance in Bacteria
- Bacterial Genetics and Biotechnology
- Clostridium difficile and Clostridium perfringens research
- Microbial Natural Products and Biosynthesis
- X-ray Diffraction in Crystallography
- Microscopic Colitis
- Crystallization and Solubility Studies
- Bacteriophages and microbial interactions
- Antibiotic Use and Resistance
- RNA and protein synthesis mechanisms
- Coastal wetland ecosystem dynamics
- Bacterial Identification and Susceptibility Testing
- Cancer therapeutics and mechanisms
- Helicobacter pylori-related gastroenterology studies
- Bioactive Compounds and Antitumor Agents
- Pharmaceutical and Antibiotic Environmental Impacts
- Gut microbiota and health
- Pharmacological Effects of Natural Compounds
- Glycosylation and Glycoproteins Research
- Computational Drug Discovery Methods
- Antibiotics Pharmacokinetics and Efficacy
- Antimicrobial Resistance in Staphylococcus
- Peptidase Inhibition and Analysis
- Antimicrobial Peptides and Activities
- Aeolian processes and effects
Novartis (United States)
2009-2022
Novartis (Switzerland)
2009-2015
Novartis Institutes for BioMedical Research
2009
South Florida Water Management District
2000-2008
Harvard University
1997-2003
University of California, San Francisco
2002
University of Wisconsin–Madison
1996-1997
All cells have stress response pathways that maintain homeostasis in each cellular compartment. In the Gram-negative bacterium Escherichia coli, sigma(E) pathway responds to protein misfolding envelope. The signal is transduced across inner membrane cytoplasm via RseA, anti-sigma factor inhibits transcriptional activity of sigma(E). Stress-induced activation requires regulated proteolysis RseA. this report we show RseA degraded by sequential proteolytic events controlled membrane-anchored...
We identified the thiomuracins, a novel family of thiopeptides produced by rare-actinomycete bacterium typed as Nonomuraea species, via screen for inhibition growth bacterial pathogen Staphylococcus aureus. Thiopeptides are class macrocyclic, highly modified peptides that decorated thiazoles and defined central six-membered heterocyclic ring system. Mining genomes thiopeptide-producing strains revealed elusive biosynthetic route this antibiotics. The chromosomally encoded, ribosomally...
Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of large intestine and produces toxins. This results in range syndromes from mild diarrhea to severe toxic megacolon death. Alarmingly, prevalence severity C. infection are increasing; thus, associated morbidity mortality rates rising. 4-Aminothiazolyl analogues antibiotic natural product GE2270 A (1) were designed, synthesized, optimized for treatment infection. The medicinal chemistry effort...
Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is semisynthetic thiopeptide with potency against C. in vitro. In this phase 2 exploratory study, we compared the safety and efficacy (based on noninferiority analysis) of to those vancomycin used adults primary episodes or first moderate infection. Patients were randomized receive 200 mg 125 four times daily 10 days....
Current treatments for Clostridium difficile infection include vancomycin, metronidazole and fidaxomicin. LFF571 is an experimental agent undergoing evaluation in humans the treatment of moderate C. infection. Reduced susceptibility to fidaxomicin or vitro can be mediated by single point mutations genes encoding targets, whereas mechanism(s) mediating reduced vancomycin remains elusive. To further characterize mechanisms reducing vitro, selections via serial passage at low cell density were...
The inherent difficulty of discovering new and effective antibacterials the rapid development resistance particularly in Gram-negative bacteria, illustrates urgent need for methods that enable rational drug design. Here we report 3D imaging cluster Time-of-Flight secondary ion mass spectrometry (ToF-SIMS) as a label-free approach to chemically map small molecules aggregated single Escherichia coli cells, with ∼300 nm spatial resolution high chemical sensitivity. feasibility quantitative...
Staphylococcus aureus and a number of other Gram-positive organisms harbour two genes (murA murZ) encoding UDP-N-acetylglucosamine enolpyruvyl transferase activity for catalysing the first committed step peptidoglycan biosynthesis. We independently inactivated murA murZ in S. established that either can sustain viability. Purification characterization MurA MurZ enzymes indicated they are biochemically similar vitro, consistent with overall structures predicted isozymes by molecular...
ABSTRACT The prototypical type II fatty acid synthesis (FAS) pathway in bacteria utilizes two distinct classes of β-ketoacyl synthase (KAS) domains to assemble long-chain acids, the KASIII domain for initiation and KASI/II elongation. central role FAS bacterial viability virulence has stimulated significant effort toward developing KAS inhibitors, particularly against β-acetoacetyl-acyl carrier protein (ACP) FabH. Herein, we show that opportunistic pathogen Pseudomonas aeruginosa does not...
LFF571 is a novel semisynthetic thiopeptide antibiotic with potent activity against variety of Gram-positive pathogens, including Clostridium difficile. In vivo efficacy was compared to vancomycin in hamster model C. difficile infection (CDI). Infection induced Golden Syrian hamsters using toxigenic strain Treatment started 24 h postinfection and consisted saline, vancomycin, or LFF571. Cox regression used analyze survival data from cohort animals evaluated across seven serial experimental...
The effects of surface (aboveground) and peat (belowground) fire on a number soil constituents were examined within hydrologically altered marsh in the northern Florida Everglades. Peat resulted losses total carbon (TC), nitrogen (TN), organic phosphorus (Po), while inorganic (Pi) calcium (TCa) concentrations increased. In addition, led to more pronounced vertical gradient constituent between upper lower layers. Surface also affected constituents, but impacts small relative fire. physical...
Escherichia coli hlyCABD operons encode the polypeptide component (Hly A) of an extracellular cytolytic toxin, as well proteins required for its acylation (HlyC) and sec-independent secretion (HlyBD). Previous reports suggested that E. protein RfaH is wild-type hemolysin expression, either by positively activating hly transcript initiation (M. J. A. Bailey, V. Koronakis, T. Schmoll, C. Hughes, Mol. Microbiol. 6:1003-1012, 1992) or promoting proper insertion export machinery in outer membrane...
We identified the fatty acid synthesis (FAS) initiation enzyme in Pseudomonas aeruginosa as FabY, a β-ketoacyl synthase KASI/II domain-containing that condenses acetyl coenzyme A (acetyl-CoA) with malonyl-acyl carrier protein (ACP) to make FAS primer β-acetoacetyl-ACP accompanying article (Y. Yuan, M. Sachdeva, J. A. Leeds, and T. C. Meredith, Bacteriol. 194:5171-5184, 2012). Herein, we show growth defects stemming from deletion of fabY can be suppressed by supplementation media exogenous...
ABSTRACT LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity against Clostridium difficile due to inhibition translation. Single-step mutants C. with reduced susceptibility were selected at frequencies <4.5 × 10 −11 1.2 −9 . Sequencing revealed G260E substitution in thiopeptide-binding pocket elongation factor Tu. Importantly, this mutation did not confer cross-resistance clinically used antimicrobials....
Escherichia coli hlyCABD operons encode the polypeptide component (HlyA) of an extracellular cytolytic toxin as well proteins required for its acylation (HlyC) and sec-independent secretion (HlyBD). The E. protein RfaH is wild-type hemolysin expression at level transcript elongation (J. A. Leeds R. Welch, J. Bacteriol. 178:1850-1857, 1996). also transcription levels mRNA from promoter-distal genes in rfaQ-K, traY-Z, rplK-rpoC gene clusters, supporting role transcriptional elongation. All or...
4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving physicochemical properties (e.g., aqueous solubility chemical stability) 4-aminothiazolyl template while in vitro vivo antibacterial activity. Structure–activity relationships defined, efficacy profiles improved over those previous 1. These studies identified novel, potent,...
4-Aminothiazolyl analogues of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. The aminothiazole-based chemical template was stability, its decomposition revealed a novel, structurally simplified, des-thiazole analogue 1. Subsequent stabilization 4-aminothiazolyl functional motif achieved initial structure activity relationships defined.
Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications 1 included removing C2-C7 side chain, derivatizing C84 epoxide region, altering C44 hydroxyphenylalanine motif. The resulting derivatives simplified stabilized structure evaluated for antibacterial activity relative 1. improved organic solubility facilitated isolation yields from fermentation broths...
Clostridium difficile infection causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, the recurrence of after therapy remains a problem. LFF571 is novel thiopeptide antibacterial that shows in vitro potency against C. comparable to or greater than other clinically used antibiotics. Here, we compare pharmacokinetics (PK) vancomycin patients as part an early efficacy study. This multicenter,...
LYS228 is a novel monobactam with potent activity against Enterobacteriaceae stable to metallo-β-lactamases (MBLs) and serine carbapenemases, including Klebsiella pneumoniae carbapenemases (KPCs), resulting in potency the majority of extended-spectrum β-lactamase (ESBL)-producing carbapenem-resistant strains tested. Overall, demonstrated 271 strains, multidrug-resistant isolates. Based on MIC90 values, (MIC90, 1 μg/ml) was ≥32-fold more active those than were aztreonam, ceftazidime,...
Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates resistance, driven largely by target-based mutations in the GyrA/ParC resistance determining region, eroded utility threaten future use this vital class antibiotics. Herein we describe optimization a series 4-(aminomethyl)quinolin-2(1H)-ones, exemplified 34, inhibit IV...