A5079915342- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- RNA modifications and cancer
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Cancer-related gene regulation
- Neurological diseases and metabolism
- RNA and protein synthesis mechanisms
- Genomics and Phylogenetic Studies
- Microbial Natural Products and Biosynthesis
- Microbial Metabolism and Applications
- Synthesis and biological activity
- Synthesis and Reactions of Organic Compounds
- Computational Drug Discovery Methods
- Enzyme Production and Characterization
- Synthesis and Characterization of Heterocyclic Compounds
- Cancer Research and Treatments
- Microbial Community Ecology and Physiology
- Bacterial Genetics and Biotechnology
- Microwave-Assisted Synthesis and Applications
- Digestive system and related health
- Cancer therapeutics and mechanisms
- Carbohydrate Chemistry and Synthesis
- Bacteriophages and microbial interactions
- Cancer Mechanisms and Therapy
University of Cambridge
2012-2022
MRC Laboratory of Molecular Biology
2022
Centro Hospitalar de Lisboa Ocidental
2021
University of Coimbra
2005-2015
Centro de Neurociências e Biologia Celular
2014
Abstract A novel four-step pathway identified recently in mycobacteria channels trehalose to glycogen synthesis and is also likely involved the biosynthesis of two other crucial polymers: intracellular methylglucose lipopolysaccharides exposed capsular glucan. The structures three intervening enzymes - GlgB, GlgE TreS were reported, providing first templates for rational drug design. Here we describe structural characterization fourth enzyme pathway, mycobacterial maltokinase (Mak),...
Reactive oxygen species (ROS)-mediated oxidative stress and DNA damage have recently been recognized as contributing to the efficacy of most bactericidal antibiotics, irrespective their primary macromolecular targets. Inhibitors targets involved in both combating well being required for vivo survival may exhibit powerful synergistic action. This study demonstrates that de novo arginine biosynthetic pathway Mycobacterium tuberculosis (Mtb) is up-regulated early response stress-elevating agent...
Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted development synchrotron radiation sources. Structures known drugs or inhibitors were used to guide leads. The growth high-throughput screening during late 1980s early 1990s pharmaceutical industry chemical libraries hundreds thousands compounds molecular weight approximately 500 Da was...
Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, treat result in accelerated function decline premature death. There therefore an urgent need develop novel antibiotics improved efficacy. tRNA (m1G37) methyltransferase (TrmD) promising target for antibiotics. It...
Tuberculosis (TB) remains a leading cause of mortality among infectious diseases worldwide. InhA has been the focus numerous drug discovery efforts as this is target first line pro-drug isoniazid. However, with resistance to becoming more common, aim find new clinical candidates that directly inhibit enzyme and do not require activation by catalase peroxidase KatG, thus circumventing majority mechanisms. In work, screening validation fragment library are described, development hits using...
A low-G+C-content Gram-positive bacterium, designated CV53 T , phylogenetically related to species of the genus Bacillus was isolated from a highly alkaline non-saline groundwater environment (pH 11.4). This organism comprised rod-shaped cells, aerobic, did not display spore formation, catalase- and oxidase-negative, had an optimum growth temperature 40 °C pH approximately 7.0–8.5. Optimal observed in absence NaCl, but occur at NaCl concentrations up 3.0 %. The strain possessed A1 γ -type...
Mycobacterium phenotypic hits are a good reservoir for new chemotypes the treatment of tuberculosis. However, absence defined molecular targets and modes action could lead to failure in drug development. Therefore, combination ligand-based structure-based chemogenomic approaches followed by biophysical biochemical validation have been used identify tuberculosis hits. Our approach identified EthR InhA as several hits, with some showing dual activity against these proteins. From 35 predicted...
The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition ArgJ with Pranlukast was found clear chronic M. infection a mouse model. Enzymes arginine biosynthetic have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, ligandability four ArgB, ArgC, ArgD and ArgF is...
Abstract Background Maltose-1-phosphate was detected in Mycobacterium bovis BCG extracts the 1960's but a maltose-1-phosphate synthetase (maltokinase, Mak) only much later purified from Actinoplanes missouriensis , allowing identification of mak gene. Recently, this metabolite proposed to be intermediate pathway linking trehalose with synthesis glycogen M. smegmatis . Although tuberculosis H37Rv gene (Rv0127) considered essential for growth, no mycobacterial Mak has, date, been...
Covering: up to the end of 2011
Abstract Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 reading frame during protein translation represents attractive potential target for development new antibiotics. Here, we describe application a structure-guided fragment-based drug discovery approach design class...
Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible treat due the intrinsic antibiotic resistance leading lung malfunction and eventually death. Therefore, there is an urgent need develop new drugs against novel targets in Mab overcome drug subsequent treatment failure. In study, SAICAR synthetase (PurC) from was identified promising target for antibiotics. An in-house fragment library...
Mycobacteria synthesize unique polysaccharides that regulate fatty acid synthesis, namely the methylglucose lipopolysaccharide (MGLP) and methylmannose polysaccharide. Glucosyl–(1→2)–glycerate is found at reducing end of MGLP. The mycobacterial gene encoding a glucosyl-3-phosphoglycerate synthase (GpgS), primarily in actinobacteria sharing very low amino identity with known homo-functional GpgSs, has been identified. This annotated as an inverting family 2 glycosyltransferase unknown...
ABSTRACT Mycobacterium hassiacum is a rapidly growing mycobacterium isolated from human urine and so far the most thermophilic among mycobacterial species. Its thermotolerance phylogenetic relationship to M. tuberculosis render its proteins attractive tools for crystallization structure-guided drug design. We report draft genome sequence of DSM 44199.
Mycobacteria synthesize intracellular methylglucose lipopolysaccharides (MGLP) proposed to regulate fatty acid synthesis. Although their structures have been elucidated, the identity of most biosynthetic genes remains unknown. The first step in MGLP biosynthesis is catalyzed by a glucosyl-3-phosphoglycerate synthase (GpgS, Rv1208 Mycobacterium tuberculosis H37Rv). However, typical phosphatase (GpgP, EC3.1.3.70) for dephosphorylation glucosylglycerate, was absent from mycobacterial genomes....
The interaction between <italic>Mycobacterium tuberculosis</italic> EthR and its operator DNA has been studied by native mass spectrometry, revealing an interesting stoichiometry.
Abstract Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, its biosynthetic pathway has raised substantial interest as drug target against multiple pathogens including Mycobacterium tuberculosis . The biosynthesis of CoA performed five steps, with the second third steps being catalysed vast majority prokaryotes, M. , by single bifunctional protein, CoaBC. Depletion CoaBC was found to be bactericidal Here we report first...