A5043244950- Antibiotic Resistance in Bacteria
- Bacterial Genetics and Biotechnology
- Microbial Natural Products and Biosynthesis
- RNA and protein synthesis mechanisms
- Antimicrobial Resistance in Staphylococcus
- Antibiotic Use and Resistance
- Antibiotics Pharmacokinetics and Efficacy
- Microbial Metabolism and Applications
- Bacterial biofilms and quorum sensing
- Plant biochemistry and biosynthesis
- RNA modifications and cancer
- Antimicrobial Peptides and Activities
- HIV Research and Treatment
- Cytomegalovirus and herpesvirus research
- Cancer therapeutics and mechanisms
- Peptidase Inhibition and Analysis
- Bacterial Identification and Susceptibility Testing
- Neurological diseases and metabolism
- Immune Response and Inflammation
- Drug Transport and Resistance Mechanisms
- Bacteriophages and microbial interactions
- Salmonella and Campylobacter epidemiology
- Escherichia coli research studies
- Chemical Reaction Mechanisms
- Porphyrin Metabolism and Disorders
Merck & Co., Inc., Rahway, NJ, USA (United States)
2014-2025
United States Military Academy
2019-2025
Novartis (United States)
2018-2020
Novartis (Switzerland)
2010-2019
Novartis Institutes for BioMedical Research
2013-2019
Merck (Japan)
2013
Harvard University
2004-2008
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded biosynthetic gene clusters. Information about these clusters, is currently dispersed throughout the literature, making it difficult exploit. To facilitate consistent systematic deposition retrieval data on we propose Minimum a Biosynthetic Gene cluster (MIBiG) standard.
Significance The spread of multidrug-resistant infections demands antibiotic development. Although new antibiotics targeting gram-positive bacteria have been developed, it has more than 50 y since a class gram-negative approved for clinical use. strong outer membrane permeability barrier makes difficult compounds to reach intracellular targets, contributing greatly the lack this microbes. Here, we describe compound, MRL-494, that inhibits assembly proteins into by an essential member...
ABSTRACT The fungal secondary metabolite gliotoxin produced by Aspergillus fumigatus has been hypothesized to be important in the development of invasive aspergillosis. In this study, we addressed hypothesis disrupting a nonribosomal peptide synthetase (NRPS) (encoded gliP ) predicted involved production. Mutants with disrupted locus failed produce gliotoxin, which confirmed role NRPS encoded biosynthesis. We found no morphological, developmental, or physiological defects Δ mutant strains....
The purple chromobacterial pigment violacein arises by enzymatic oxidation and coupling of two molecules l-tryptophan to give a rearranged pyrrolidone-containing scaffold in the final pigment. We have purified five contiguously encoded proteins VioA-E after expression Escherichia coli demonstrate full 14-electron pathway yield chromophore. flavoenzyme VioA heme protein VioB work conjunction oxidize dimerize nascent product that can default off metabolite chromopyrrolic acid. In presence...
New inhibitors of wall teichoic acid biosynthesis restore susceptibility drug-resistant staphylococci to β-lactam antibiotics.
The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. production β-lactamase key mechanism contributing imipenem in P. aeruginosa. Relebactam novel inhibitor, active against class A C β-lactamases, that shown restore susceptibility. In series studies, we assessed the interaction relebactam with mechanisms involved carbapenem what extent might overcome non-susceptibility.
The fungal metabolite gliotoxin has a redox-active disulfide bridge spanning carbons 3 and 6 of diketopiperazine (DKP) scaffold. proposed DKP synthetase, GliP, from Aspergillus fumigatus Af293, is three module (A1-T1-C1-A2-T2-C2-T3) 236 kDa protein that can be overproduced in soluble form Escherichia coli. Once primed on its thiolation domains with phosphopantetheine prosthetic groups, GliP activates tethers l-Phe T1 l-Ser T2, before generating the l-Phe-l-Ser-S-T2 dipeptidyl enzyme...
The outer membrane (OM) of Gram-negative bacteria forms a robust permeability barrier that blocks entry toxins and antibiotics. Most OM proteins (OMPs) assume β-barrel fold, some form aqueous channels for nutrient uptake efflux intracellular toxins. Bam machine catalyzes rapid folding assembly OMPs. Fidelity OMP biogenesis is monitored by the σE stress response. When defects arise, proteases DegS RseP act sequentially to liberate into cytosol, enabling it activate transcription regulon....
Gram-negative bacteria are notoriously more resistant to antibiotics than Gram-positive bacteria, primarily due the presence of outer membrane and a plethora active efflux pumps. However, potency also varies dramatically between different pathogens, suggesting major mechanistic differences in how penetrate permeability barriers.
Siderophores are key virulence factors that allow bacteria to grow in iron-restricted environments. The Gram-positive pathogen Staphylococcus aureus is known produce four siderophores for which genetic and/or structural data unknown. Here we characterize the gene cluster responsible producing prevalent siderophore staphyloferrin A. In addition expressing heterologous host Escherichia coli, confers ability synthesize siderophore, reconstituted A biosynthesis vitro by and purifying two enzymes...
Modern medicine is founded on the discovery of penicillin and subsequent small molecules that inhibit bacterial peptidoglycan (PG) cell wall synthesis. However, new chemically mechanistically distinct classes PG inhibitors has become exceedingly rare, prompting speculation intracellular enzymes involved in precursor synthesis are not 'druggable' targets. Here, we describe a β-lactam potentiation screen to identify augment activity β-lactams against methicillin-resistant Staphylococcus aureus...
Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction therefore an important cure strategy. Some nonnucleoside reverse transcriptase inhibitors induce selective cytotoxicity in vitro require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1–infected cell kill potency at clinically...
ABSTRACT Coenzyme A (CoA) plays a central and essential role in all living organisms. The pathway leading to CoA biosynthesis has been considered an attractive target for developing new antimicrobial agents with novel mechanisms of action. By using arabinose-regulated expression system, the essentiality coaBC , single gene encoding bifunctional protein catalyzing two consecutive steps converting 4′-phosphopantothenate 4′-phosphopantetheine, was confirmed Escherichia coli . Utilizing this...
ABSTRACT Bacterial resistance to antibiotics continues grow and pose serious challenges, while the discovery rate for new declines. Kibdelomycin is a recently discovered natural-product antibiotic that inhibits bacterial growth by inhibiting DNA replication enzymes gyrase topoisomerase IV. It was reported be broad-spectrum aerobic Gram-positive agent with selective inhibition of anaerobic bacterium Clostridium difficile . We have extended profiling kibdelomycin using over 196 strains...
Gram-negative bacteria provide a particular challenge to antibacterial drug discovery due their cell envelope structure. Compound entry is impeded by the lipopolysaccharide (LPS) of outer membrane (OM), and those molecules that overcome this barrier are often expelled multidrug efflux pumps. Understanding how permeability affect ability compound reach its target paramount translating in vitro biochemical potency cellular bioactivity. Herein, suite Pseudomonas aeruginosa strains were...
Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that lead to eradication of persistent viral reservoirs in people living with (PLWH) remains an outstanding challenge achieving cure. Utilizing a phenotypic screen, we identified novel chemical class capable killing infected peripheral blood mononuclear cells. Tool compounds ICeD-1 ICeD-2 ("inducer cell death-1 2"), optimized for potency...
Despite the success of combination antiretroviral therapy (cART) to suppress HIV replication, persists in a long-lived reservoir that can give rise rebounding viremia upon cART cessation. The translationally active consists HIV-infected cells continue produce viral proteins even presence cART. These are implicated resultant cessation and likely contribute chronic immune activation people living with (PLWH) on Methodologies quantify needed. Here, an automated immunocytochemistry (ICC) assay...
Acinetobacter baumannii is a Gram-negative pathogen responsible for pneumonia and wound, bloodstream, urinary tract infections, particularly patients in intensive care units. Using phenotypic screening we have identified novel class of small molecule inhibitors that potent highly selective antibacterial activity against baumannii. Resistance selection the molecular target as MsbA, an essential ABC transporter functions by flipping lipid A across inner membrane most gram-negative bacteria....
Isoprenoids are a class of ubiquitous organic molecules synthesized from the five-carbon starter unit isopentenyl pyrophosphate (IPP). Comprising more than 30,000 known natural products, isoprenoids serve various important biological functions in many organisms. In bacteria, undecaprenyl is absolutely required for formation cell wall peptidoglycan and other surface structures, while ubiquinones menaquinones, both containing an essential prenyl moiety, key electron carriers respiratory energy...
The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) acyltransferase LpxA, first enzyme in pathway. We show genetically that antibacterial activities compounds efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, inhibited enzymatic reaction vitro. Intriguingly, using biochemical,...