A5009097110- Bacterial Genetics and Biotechnology
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Antibiotic Resistance in Bacteria
- Bacteriophages and microbial interactions
- Biochemical and Molecular Research
- Protein Structure and Dynamics
- Pneumonia and Respiratory Infections
- Antimicrobial Resistance in Staphylococcus
- Amino Acid Enzymes and Metabolism
- Peptidase Inhibition and Analysis
- Glycosylation and Glycoproteins Research
- Streptococcal Infections and Treatments
- Chemical Synthesis and Analysis
- Carbohydrate Chemistry and Synthesis
- Microbial Natural Products and Biosynthesis
- Cancer therapeutics and mechanisms
- Lipid Membrane Structure and Behavior
- Genomics and Phylogenetic Studies
- Antimicrobial Peptides and Activities
- Microbial Metabolic Engineering and Bioproduction
- Escherichia coli research studies
- Click Chemistry and Applications
- Enzyme Production and Characterization
- RNA modifications and cancer
University of Warwick
2015-2024
National University of Singapore
2024
Coventry (United Kingdom)
2015-2022
Columbia University
2022
Columbia University Irving Medical Center
2021
IE University
2017
Yokohama City University
2002-2009
Hammersmith Hospital
2006-2008
United Nations Industrial Development Organization
2008
University of Illinois Urbana-Champaign
2008
Bacteria exhibit a myriad of different morphologies, through the synthesis and modification their essential peptidoglycan (PG) cell wall. Our discovery fluorescent D-amino acid (FDAA)-based PG labeling approach provided powerful method for observing how these morphological changes occur. Given that is unique to bacterial cells common target antibiotics, understanding precise mechanism(s) incorporation (F)DAA-based probes crucial determinant in role biology could provide valuable tool...
Homeostatic regulation of the partial pressure CO2 (PCO2) is vital for life. Sensing pH has been proposed as a sufficient proxy determination PCO2 and direct CO2-sensing largely discounted. Here we show that connexin 26 (Cx26) hemichannels, causally linked to respiratory chemosensitivity, are directly modulated by CO2. A 'carbamylation motif', present in CO2-sensitive connexins (Cx26, Cx30, Cx32) but absent from CO2-insensitive (Cx31), comprises Lys125 four further amino acids orient towards...
5-Carboxymethyl-2-hydroxymuconate isomerase (CHMI) and 4-oxalocrotonate tautomerase (4-OT) are enzymes that catalyze the isomerization of unsaturated ketones. They share a common enzyme mechanism, although they show preference for different substrates. There is no apparent sequence homology between enzymes. To investigate molecular mechanism basis their substrate specificity, we have determined crystal structures two at high resolution. 4-OT hexameric, with subunits arranged 32 symmetry....
Understanding the molecular basis of bacterial cell wall assembly is paramount importance in addressing threat increasing antibiotic resistance worldwide. Streptococcus pneumoniae presents a particularly acute problem this respect, as it capable rapid evolution by homologous recombination with related species. Resistant strains selected treatment β-lactams express variants target enzymes that do not recognize drugs but retain their activity building, despite antibiotics being mimics natural...
D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, chemical mechanistic studies here we show that the inhibition ligase by proceeds via distinct phosphorylated form drug. This insight reveals bimodal mechanism action for single on different enzyme has significance design future inhibitor molecules based this structure.
Abstract Biological characterisation of membrane proteins lags behind that soluble proteins. This reflects issues with the traditional use detergents for extraction, as surrounding lipids are generally lost, adverse structural and functional consequences. In contrast, styrene maleic acid (SMA) copolymers offer a detergent-free method biological solubilisation to produce SMA-lipid particles (SMALPs) containing together their lipid environment. We report development reverse-phase LC-MS/MS...
The crystal structure of penicillin binding protein 4 (PBP4) from Escherichia coli, which has both DD-endopeptidase and DD-carboxypeptidase activity, is presented. PBP4 one 12 proteins in E. coli involved the synthesis maintenance cell wall. model contains a domain similar to known structures, but includes large insertion folds into domains with unique folds. structures covalently attached five different antibiotics presented here show active site residues are unmoved compared apoprotein,...
Airway infection by the Gram-positive pathogen Streptococcus pneumoniae (Sp) leads to recruitment of neutrophils but limited bacterial killing these cells. Co-colonization Sp and a Gram-negative species, Haemophilus influenzae (Hi), provides sufficient stimulus induce neutrophil complement-mediated clearance from mucosal surface in murine model. Products Hi, not Sp, also promote ex vivo neutrophil-enriched peritoneal exudate Here we identify Hi as its peptidoglycan. Enhancement...
Surfactant-mediated removal of proteins from biomembranes invariably results in partial or complete loss function and disassembly multi-protein complexes. We determined the capacity styrene-co-maleic acid (SMA) co-polymer to remove components cell division machinery membrane drug-resistant staphylococcal cells. SMA-lipid nanoparticles solubilized FtsZ-PBP2-PBP2a complexes intact cells, demonstrating close physical proximity these within lipid bilayer. Exposure bacteria (-)-epicatechin...
New optically pure helicate-like architectures are extremely active against cancer cell lines, with IC<sub>50</sub> values as low 40 nM, but nearly three orders of magnitude less healthy cells. There is also toxicity to microbes and amoeba.
Tuberculosis (TB) is responsible for enormous global morbidity and mortality, current treatment regimens rely on the use of drugs that have been in more than 40 years. Owing to widespread resistance these therapies, new are desperately needed control TB disease burden. Herein, we describe rapid synthesis analogues sansanmycin uridylpeptide natural products represent promising drug leads. The compounds exhibit potent selective inhibition Mycobacterium tuberculosis, etiological agent TB, both...
Significance The peptidoglycan layer is a core component of the bacterial cell envelope that provides barrier to environment and protection from osmotic shock. During division, bacteria must break rebuild enable separation daughter cells. In E. coli , two three amidases responsible (AmiA AmiB) are regulated by single periplasmic activator (EnvC) is, itself, controlled an atypical ABC transporter (FtsEX) tethered cytoplasmic septal Z-ring. Here we define structural basis for interaction FtsEX...
AmiA and AmiB are peptidoglycan-hydrolyzing enzymes from Escherichia coli that required to break the peptidoglycan layer during bacterial cell division maintain integrity of envelope. In vivo, activity is tightly controlled through their interactions with membrane-bound FtsEX–EnvC complex. Activation requires access a groove in amidase-activating LytM domain EnvC which gated by ATP-driven conformational changes Here, we present high-resolution structure isolated protein, confirming it...
Abstract Pattern recognition receptors are central to the responsiveness of various eukaryotic cell types when they encounter pathogen-associated molecular patterns. IFN-γ is a cytokine that elevated in humans and other animals with bacterial infection enhances LPS-induced production antibacterial mediators by macrophages. Mice lacking pattern receptor, TLR4, respond very poorly stimulation LPS, but administration has been described as restoring apparent sensitivity this stimulatory ligand....
MurM is an aminoacyl ligase that adds l-serine or l-alanine as the first amino acid of a dipeptide branch to stem peptide lysine pneumococcal peptidoglycan. activity essential for clinical penicillin resistance. Analysis peptidoglycan from highly penicillin-resistant Streptococcus pneumoniae strain 159 revealed in vivo and vitro, presence appropriate acyl-tRNA, MurM(159) alanylated epsilon-amino group preference its serylation. However, contrast, identical analyses penicillin-susceptible...