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Cancer Informatics
Published in Trevor F. Cox, Medical Statistics for Cancer Studies, 2022
In our last analysis, we look at mutations in the genes. The mutation data is stored in MAF files (Mutation Annotation Format) which are downloaded in like manner to the expression data. The Bioconductor package maftools is used to analyse the data. The functions getGeneSummary() and getSampleSummary() summarise the mutations. There are five types of mutation recorded: Missense mutation: a change in a base pair that leads to a different amino acid being used in the resulting protein.Nonsense mutation: a change in a base pair that leads to a premature stop codon.Nonstop mutation: a change in a base pair in a stop codon leading to further inappropriate translation.Splice site: an alteration at the boundary af an exon and an intron.Translation start site: an alteration of the start site of translation of a gene.
Retapamulin
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Retapamulin is a semisynthetic pleuromutilin antibiotic. This drug is usually bacteriostatic in action, but may become bactericidal at higher concentrations. It inhibits protein synthesis by (I) binding a component of the bacterial ribosome that affects normal 50S subunit formation, (II) blocking ribosomal P-site interactions, and (III) inhibiting peptidyl transferase. The interaction with bacterial ribosomes is unique from other topical antibiotics and prevents cross-resistance (3). Retapamulin is indicated for the topical treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes and secondarily infected traumatic lesions (1).
Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Selective toxicity against bacteria can be achieved in drugs that target ribosomal RNA, and inhibiting different stages of the translation process, due to the fact that prokaryotic ribosomes differ in structure to those found in eukaryotic cells. The bacterial ribosome is a 70S particle, composed of a 30S subunit which binds to mRNA and initiates protein synthesis, and a 50S subunit, which binds to the 30S-mRNA complex to make the ribosome. The ribosome has two main binding sites: the peptide site (P site) binds the tRNA bearing the peptide chain, and the acceptor aminoacyl site (A site) binds the tRNA bearing the next amino acid in the protein sequence, to which the peptide chain will be transferred. Eukaryotic cells have bigger ribosomes made of a 60S large subunit and a 40S small subunit.
Synthetic engineered bacteria for cancer therapy
Published in Expert Opinion on Drug Delivery, 2023
The complicated pathophysiology of tumors highlights the need for new anticancer therapies to compensate for the shortcomings of traditional therapies such as chemotherapy, radiotherapy, and phototherapy. Recently, bacteriotherapy has demonstrated profound effects on tumors, thanks to its self-propulsion, natural tumor core colonization, and immune response stimulation characteristics. In this review, we summarized recent progress on the synthetic methods for bacterial modifications and briefly described biomedical applications of engineered bacteria in the treatment of cancer. These advanced synthetic techniques endow bacteria with superior abilities in tumor treatment to achieve desired outcomes through the following principles. Bacteria induce lower immunogenicity and exhibit safer, more targeted site-specific localization with precise spatial and temporal control properties through these sophisticated synthetic approaches. They can also be engineered to release various payloads both extracellularly and intracellularly against discrete disease processes through secretions, transformations, and lysis, leading to remarkable treatment efficacy.
Strengths and caveats of identifying resistance genes from whole genome sequencing data
Published in Expert Review of Anti-infective Therapy, 2022
Brian M. Forde, David M. P. De Oliveira, Caitlin Falconer, Bianca Graves, Patrick N. A. Harris
Bacterial target site modifications are a common mechanism by which bacteria acquire AMR . Mutations resulting in target site modifications act to either prevent the binding of the antimicrobial or reduce the affinity of the respective binding interaction. Modification of target sites encompass mechanisms pertaining to: 1) enzyme modification (fluroquinolone resistance: gyrA and parC mutations) [19–21]; 2) ribosomal modification (e.g. erm-encoded 23S rRNA methyltransferases: macrolide and macrolidelincosamide-streptogramin B resistance) [22,23]; and 3) variations in cell wall precursor structures (glycopeptide resistance: van gene clusters; β-lactam resistance: mecA; polymyxin resistance: mgrB inactivation, pmrB mutation) [24–28]. Coalesced with these mechanisms, antibiotic inactivation through antibiotic drug-modifying enzymes are additional AMR strategies that act to irreversibly render antibiotics inoperative. Both β-lactamases and aminoglycoside modifying enzymes (AMEs) are two of the most well-characterized antibiotic inactivation systems. So far, over 2600 β-lactamases have been characterized, facilitating the hydrolytic-cleavage (and inactivation) of penicillins, cephalosporins, monobactams, and carbapenems [29,30]. For aminoglycoside resistance, AME encoding genes located on either plasmids, transposons, or in the chromosome, catalyze hydroxyl or amino acid modifications on aminoglycoside class antibiotics, reducing the binding affinity of the aminoglycosides to the ribosomal subunit binding site [31].
Phosphoglycerate dehydrogenase (PHGDH) inhibitors: a comprehensive review 2015–2020
Published in Expert Opinion on Therapeutic Patents, 2021
Quentin Spillier, Raphaël Frédérick
In 2016, two allosteric sites on PHGDH were computationally identified by Wang and coworkers using a cavity prediction algorithm. The first (site I), sharing at least five amino acids with the enzyme active site (Gly 78, Val 79, Asp 80, Asn 81 and Val 82), is located at the interface of the enzyme active site and the Rossman fold, whereas the second (site II), smaller, was identified in the substrate-binding cavity. Virtual screening experiments at these allosteric sites led to the identification of 98 compounds of which 2 compounds, 71 (PKUMDL-WQ-2201) and 72 (PKUMDL-WQ-2101) (Figure 10) were shown to bind PHGDH by surface plasmon resonance (SPR) experiments[44]. Competition experiments as well as site-directed mutagenesis confirmed the interactions between 72 and site I as well as 71 with site II. In addition, cellular assays demonstrated the ability of these two molecules to selectively reduce the proliferation of cancer lines overexpressing PHGDH as well as their potential to significantly reduce intracellular serine and glycine flux. Interestingly, these two inhibitors were also documented to reduce in vivo the growth of tumors overexpressing PHGDH. This series of inhibitors is patented [45,46].