A5074383030- Microbial Natural Products and Biosynthesis
- Genomics and Phylogenetic Studies
- Microbial Metabolic Engineering and Bioproduction
- Enzyme Structure and Function
- Biochemical and Structural Characterization
- Plant biochemistry and biosynthesis
- Streptococcal Infections and Treatments
- Marine Sponges and Natural Products
- Carbohydrate Chemistry and Synthesis
- Enzyme Catalysis and Immobilization
- Synthetic Organic Chemistry Methods
- Cancer therapeutics and mechanisms
- Fungal Biology and Applications
- Bacterial Genetics and Biotechnology
- Gene Regulatory Network Analysis
- Photosynthetic Processes and Mechanisms
- Antibiotic Resistance in Bacteria
- Amino Acid Enzymes and Metabolism
- Neonatal and Maternal Infections
- Biochemical and Molecular Research
- RNA and protein synthesis mechanisms
- Viral gastroenteritis research and epidemiology
- CRISPR and Genetic Engineering
- Antimicrobial Resistance in Staphylococcus
- Protein Structure and Dynamics
Newcastle University
2005-2025
University of Bristol
2015-2024
At Bristol
2015-2017
Avondale University
2014
Imperial College London
2008
University of Newcastle Australia
2008
University of Birmingham
2003-2007
University of Saskatchewan
2005
Rutgers, The State University of New Jersey
2003
Brunel University of London
1997
The antibiotics nitrofurazone and nitrofurantoin are used in the treatment of genitourinary infections as topical antibacterial agents. Their action is dependent upon activation by bacterial nitroreductase flavoproteins, including <i>Escherichia coli</i> (NTR). Here we show that products reduction these NTR hydroxylamine derivatives. We nitrosoaromatics enzyme-catalyzed, with a specificity constant ∼10,000-fold greater than starting nitro compounds. This suggests groups proceeds through two...
The Diels–Alder reaction, a [4 + 2] cycloaddition of conjugated diene to dienophile, is one the most powerful reactions in synthetic chemistry. Biocatalysts capable unlocking new and efficient would have major impact. Here we present molecular-level description reaction mechanism spirotetronate cyclase AbyU, an enzyme shown here be bona fide natural Diels–Alderase. Using assays, X-ray crystal structures, simulations enzyme, reveal how linear substrate chains are contorted within AbyU active...
A commonly used strategy by microorganisms to survive multiple stresses involves a signal transduction cascade that increases the expression of stress-responsive genes. Stress signals can be integrated multiprotein signaling hub responds various effect single outcome. We obtained medium-resolution cryo–electron microscopy reconstruction 1.8-megadalton “stressosome” from Bacillus subtilis . Fitting known crystal structures components into this gave pseudoatomic structure, which had virus...
Sortases are a family of Gram-positive bacterial transpeptidases that anchor secreted proteins to cell surfaces. These include many play critical roles in the virulence pathogens such sortases attractive targets for development novel antimicrobial agents. All express "housekeeping" sortase recognizes majority containing an LP<i>X</i>TG wall-sorting motif and covalently attaches these wall peptidoglycan. Many also additional link small number proteins, often with variant motifs, either other...
Computer-aided design for synthetic biology promises to accelerate the rational and robust engineering of biological systems; it requires both detailed quantitative mathematical experimental models processes (re)design, software tools genetic DNA assembly. Ultimately, increased precision in phase will have a dramatic impact on production designer cells organisms with bespoke functions modularity. strategies require representations cells, able capture multiscale link genotypes phenotypes....
To tackle the growing problem of antibiotic resistance, it is essential to identify new bioactive compounds that are effective against resistant microbes and safe use. Natural products their derivatives are, will continue be, an important source these molecules. Sea sponges harbour a diverse microbiome co-exists with sponge, bacterial communities produce rich array metabolites for protection resource competition. For reasons, sponge microbiota constitutes potential clinically relevant...
The electron-conducting circuitry of life represents an as-yet untapped resource exquisite, nanoscale biomolecular engineering. Here, we report the characterization and structure a de novo diheme "maquette" protein, 4D2, which subsequently use to create expanded, modular platform for heme protein design. A well-folded monoheme variant was created by computational redesign, then utilized experimental validation continuum electrostatic redox potential calculations. This demonstrates how...
Streptococcus agalactiae (group B Streptococcus, GBS) is the predominant cause of early-onset infectious disease in neonates and responsible for life-threatening infections elderly immunocompromised individuals. Clinical manifestations GBS infection include sepsis, pneumonia, meningitis. Here, we describe BspA, a deviant antigen I/II family polypeptide that confers adhesive properties linked to pathogenesis GBS. Heterologous expression BspA on surface non-adherent bacterium Lactococcus...
Sustained forward migration through a fibrillar extracellular matrix requires localization of protrusive signals. Contact with fibronectin at protruding tip activates Rac1, and for linear it is necessary to dampen Rac1 activity in off-axial positions redistribute from non-protrusive membrane the leading edge. We identify interactions between Coro1C, RCC2 that focus active single protrusion. Coro1C mediates release inactive redistribution fibronectin-dependent activation. The second...
ABSTRACT Here, we report the resequencing, assembly, and annotation of two actinomycete genomes containing abyssomicin gene clusters. Kutzneria buriramensis DSM 45791 with a circular chromosome 11,681,598 bp 4 plasmids (14,175–207,548 bp) Streptomyces sp. NL15-2K 12,368,159 linear genome plasmid (11,584 bp).
Many protein domains harbour covalent intramolecular bonds that enhance their stability and resistance to thermal, mechanical proteolytic insults. Intramolecular isopeptide represent one such interaction, yet distribution across organisms has been largely unexplored. Here, we sought address this by employing a large-scale prediction of in the AlphaFold database using structural template-based software Isopeptor. Our findings reveal an extensive phyletic surface proteins resembling fibrillar...
Cyclic and acyclic nitroaryl phosphoramide mustard analogues were activated by E. coli nitroreductase, an enzyme explored in GDEPT. The more active 4-nitrobenzyl (7) showed 167 500× selective cytotoxicity toward nitroreductase-expressing V79 cells with IC50 as low 0.4 nM. This is about 100× 27× than CB1954 (1). superior activity was attributed to its better substrate (kcat/Km 19× 1) and/or excellent of released.
Sphingomyelinases C are enzymes that catalyze the hydrolysis of sphingomyelin in biological membranes to ceramide and phosphorylcholine. Various pathogenic bacteria produce secreted neutral sphingomyelinases act as membrane-damaging virulence factors. Mammalian C, which display sequence homology bacterial enzymes, involved sphingolipid metabolism signaling. This article describes first structure be determined for a member sphingomyelinase family, SmcL, from intracellular pathogen Listeria...
A pre-requisite for bacterial pathogenesis is the successful interaction of a pathogen with host. One mechanism used by broad range Gram negative pathogens to deliver effector proteins directly into host cells through dedicated type III secretion system where they modulate cell function. The cycle inhibiting factor (Cif) family proteins, identified in growing number that harbour functional systems and have wide range, arrest eukaryotic cycle. Here, crystal structures Cifs from insect...
Achieving regio-specific hydroxylation of aromatic compounds remains a major challenge in synthetic chemistry.
Adherence of bacteria to biotic or abiotic surfaces is a prerequisite for host colonization and represents an important step in microbial pathogenicity. This attachment facilitated by bacterial adhesins at the cell surface. Because their size often elaborate multidomain architectures, these polypeptides represent challenging targets detailed structural functional characterization. The multifunctional fibrillar adhesin CshA, which mediates binding both molecules other microorganisms,...
Self-healing materials with an inherent repair mechanism have been widely studied. However, the self-healing efficiencies of most can only be measured by laboratory-based experiments, which time consuming and expensive. Inspired modern machine learning approaches, we are interested in predicting efficiency new bio-hybrid materials, as part our ongoing EPSRC funded "Manufacturing Immortality" project. By modelling existing experimental data, predictive models built to forecast efficiency....
Abstract Mupirocin is a clinically important antibiotic produced by trans ‐AT Type I polyketide synthase (PKS) in Pseudomonas fluorescens . The major bioactive metabolite, pseudomonic acid A (PA−A), assembled on tetrasubstituted tetrahydropyran (THP) core incorporating 6‐hydroxy group proposed to be introduced α‐hydroxylation of the thioester acyl carrier protein (ACP) bound chain. Herein, we describe an vitro approach combining purified enzyme components, chemical synthesis, isotopic...
Antibiotic resistance is a global health crisis. New classes of antibiotics that can treat drug-resistant infections are urgently needed. To communicate this message, researchers have used antibiotic development timelines, but these often contradictory or imprecise. We conducted systematic literature review to produce an timeline incorporates the dates discovery, first use, and initial reports emergence for 38 clinically antibiotics. From our timeline, we derive lessons identifying new less...