A5003915201- Tuberculosis Research and Epidemiology
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Mycobacterium research and diagnosis
- Pneumonia and Respiratory Infections
- Microbial Natural Products and Biosynthesis
- Drug Transport and Resistance Mechanisms
- Pneumocystis jirovecii pneumonia detection and treatment
- RNA and protein synthesis mechanisms
- Glycosylation and Glycoproteins Research
- X-ray Diffraction in Crystallography
- Antibiotic Resistance in Bacteria
- Monoclonal and Polyclonal Antibodies Research
- Diagnosis and treatment of tuberculosis
- Neonatal and Maternal Infections
- CRISPR and Genetic Engineering
- Peptidase Inhibition and Analysis
- Crystallization and Solubility Studies
- Computational Drug Discovery Methods
- RNA modifications and cancer
- Legume Nitrogen Fixing Symbiosis
- Synthetic Organic Chemistry Methods
- Bacterial biofilms and quorum sensing
- Microbial Community Ecology and Physiology
- Chemical Synthesis and Analysis
University of Birmingham
2014-2024
GlaxoSmithKline (United Kingdom)
2022
University of Warwick
2013
Mycobacterium tuberculosis is a major human pathogen and the causative agent for pulmonary disease, (TB). Current treatment programs to combat TB are under threat due emergence of multi-drug extensively-drug resistant TB. Through use high throughput whole cell screening an extensive compound library number imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. bovis BCG. The IP inhibitors (1–4) demonstrated minimum inhibitory concentrations (MICs) in...
Abstract Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase ( kas ) A gene. Here, genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution a...
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...
As a result of high-throughput compound screening campaign using Mycobacterium tuberculosis -infected macrophages, new drug candidate for the treatment has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC 50 ] = 0.07 μM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs.
Abstract Mycobacterium tuberculosis is one of the global leading causes death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that have progressed through drug discovery pipeline. These compounds bicyclic nitroimidazoles act as pro-drugs, requiring activation by mycobacterial enzyme; however, precise mechanisms action active metabolite(s) unclear. Here, we identify molecular target activated pretomanid delamanid: DprE2 subunit...
Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 3 as potent inhibitors mycobacterial growth. Optimization in series led to 4, which has proven activity an vivo murine model Mtb infection. Here we identify target mode inhibition these compounds based on whole genome sequencing spontaneous resistant mutants, identified...
The lack of success in target-based screening approaches to the discovery antibacterial agents has led reemergence phenotypic as a successful approach identifying bioactive, compounds. A challenge though with this route is then identify molecular target(s) and mechanism action hits. This target identification, or deorphanization step, often essential further optimization validation studies. Direct experimental identification hit complex, precisely because properties specificity are not yet...
The human pathogen Mycobacterium tuberculosis is the causative agent of pulmonary (TB), a disease with high worldwide mortality rates. Current treatment programs are under significant threat from multi-drug and extensively-drug resistant strains M. tuberculosis, it essential to identify new inhibitors their targets. We generated spontaneous mutants in bovis BCG presence 10× minimum inhibitory concentration (MIC) compound 1, previously identified potent inhibitor mycobacterial growth culture....
Abstract High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification ‘hit’ compounds. A pre-requisite to medicinal chemistry optimisation programmes required improve drug-like properties a molecule is its mode action. Herein, we combined with biased target-specific screen. inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 been identified drugable target Mycobacterium...
DprE2 is an essential enzyme in the synthesis of decaprenylphosphoryl-β-d-arabinofuranose (DPA) and subsequently arabinogalactan, a significant new drug target for M. tuberculosis. Two compounds from GSK-177 box set, GSK301A GSK032A, were identified through Mt-DprE2-target overexpression studies. The Mt-DprE1-DprE2 complex was co-purified vitro assay developed, based on oxidation reduced nicotinamide adenine dinucleotide cofactor (NADH/NADPH). showed interesting kinetics both DprE1...
A modular synthetic approach was developed in which variation of the triplets building blocks used enabled systematic macrocyclic scaffolds prepared. The demonstrated synthesis 17 diverse natural product-like varied (12-20-membered) ring size. biological relevance chemical space explored through discovery a series macrocycles with significant antimycobacterial activity.
MmpL3, an essential mycolate transporter in the inner membrane of Mycobacterium tuberculosis (Mtb), has been identified as a target multiple, chemically diverse antitubercular drugs. However, several these molecules seem to have secondary targets and inhibit bacterial growth by more than one mechanism. Here, we describe cell-based assay that utilizes two-way regulation MmpL3 expression readily identify MmpL3-specific inhibitors. We successfully used this novel guanidine-based inhibitor from...
Abstract As a result of high-throughput compound screening campaign Mycobacterium tuberculosis infected macrophages, new preclinical drug candidate for the treatment has been identified. GSK2556286 inhibits growth within human macrophages (IC 50 = 0.07 µM), is active against extracellular bacteria in cholesterol-containing culture media and exhibits no cross-resistance with known antitubercular drugs. In addition, it shown efficacy different mouse models (TB) an adequate safety profile two...
Anti-tubercular drug discovery continues to be dominated by whole-cell high-throughput screening campaigns, enabling the rapid of new inhibitory chemical scaffolds. Target-based is a popular approach direct inhibitor with specified mode action, eliminating anti-tubercular agents against unsuitable targets. Herein, method has been developed using Mycobacterium bovis BCG identify inhibitors amino acid biosynthesis. The methodology was initially optimized known branched-chain biosynthetic...
Mycobacterium tuberculosis , the causative agent of TB is among leading causes death infectious diseases in humans. This situation has worsened due to failure BCG vaccines and increased number cases with HIV-TB coinfections drug-resistant strains.
The emergence and perseverance of drug resistant strains Mycobacterium tuberculosis (Mtb) ensures that discovery efforts remain at the forefront research. There are numerous different approaches can be employed to lead anti-tubercular agents. In this work, we endeavored optimize anthraquinone chemical scaffold a known drug, rhein, converting it from compound with negligible activity against Mtb, series compounds potent activity. Two exhibited low toxicity good liver microsome stability were...