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Telithromycin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Eric Wenzler, Keith A. Rodvold
Like macrolides, telithromycin inhibits bacterial protein synthesis by blocking the passage of nascent proteins through the 50S ribosomal exit tunnel. Unlike macrolides, telithromycin also binds the V and II domains of the 23S RNA subunit. Alterations in the domain V binding site via methylation or mutation provide certain pathogens the ability to resist the activity of macrolides (Hisanaga et al., 2005). The additional binding of telithromycin to domain II is responsible for the improved antimicrobial activity of ketolides against macrolide-resistant pathogens (Berisio et al., 2003). In addition, telithromycin has also been shown to bypass the erm gene induction pathway while other macrolides increase levels of erm methyltransferases in bacterial species carrying inducible genes (Wolter et al., 2008). Telithromycin-resistant S. pneumoniae isolates have been rarely identified, demonstrating telithromycin MICs between 2 and 8 mg/l due to multiple alterations in the 23S rRNA in addition to other resistance mechanisms (Al-Lahham et al., 2006). The global surveillance project Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) demonstrated only 0.2% of S. pneumoniae isolates collected from 1999 to 2003 to be telithromycin-resistant (Farrell and Felmingham, 2004). Macrolide-resistant staphylococci possess the msr (A) determinant, which also confers upon the organisms low-level resistance to telithromycin, although high-level resistance requires mutations in the CLpX chaperone proteolytic system (Vimberg et al., 2015).
Regulation of flagellar motility and biosynthesis in enterohemorrhagic Escherichia coli O157:H7
Published in Gut Microbes, 2022
Hongmin Sun, Min Wang, Yutao Liu, Pan Wu, Ting Yao, Wen Yang, Qian Yang, Jun Yan, Bin Yang
ClpXP protease is an ATP-dependent bipartite protease responsible for the degradation of some key regulatory proteins (such as RpoS) and aberrant translation products.99,100 ClpXP consists of a ClpP protein degradation component and a ClpX component that binds the substrate protein.101 In EHEC O157:H7, both FlhD and FlhC proteins accumulated markedly following ClpXP depletion, and their half-lives were significantly longer in the mutant cells, suggesting that ClpXP causes the degradation of FlhD and FlhC proteins, leading to the downregulation of flagellar gene expression.49 In addition, ClpXP negatively regulates the transcription of the flhD promoter through the GrlR‒GrlA system under conditions in which LEE gene expression is induced. Therefore, the ClpXP protease regulates EHEC O157:H7 motility and flagellar gene expression through two pathways, namely post-translational degradation of the FlhD/FlhC master regulator and transcriptional control of the flhDC operon through the LEE-encoded GrlR‒GrlA regulatory system.49
Afamelanotide for prevention of phototoxicity in erythropoietic protoporphyria
Published in Expert Review of Clinical Pharmacology, 2021
Debby Wensink, Margreet A.E.M. Wagenmakers, Janneke G. Langendonk
EPP (OMIM 177000) is a rare autosomal recessive inherited disorder of heme biosynthesis. Symptoms result from accumulation of protoporphyrin IX (PPIX), the photosensitizing precursor of heme, in erythroid cells [2,7]. PPIX can be activated by the blue spectrum (400–410 nm, the Soret Band) of visible light. As well as sunlight many artificial light sources can activate PPIX [9]. In most individuals (>90%) EPP is caused by mutations in the FECH gene resulting in decreased activity of ferrochelatase, the enzyme that converts PPIX to heme by incorporating ferrous iron into the tetrapyrrole ring. Rare causes of EPP are X-linked protoporphyria (XLP, OMIM 300752) [10] or mutations in the CLPX gene [11], presenting with identical phototoxic symptoms. PPIX in erythrocytes, plasma, and endothelial cells in the skin absorbs visible light (410 nm), resulting in formation of reactive oxygen species, which cause endothelial and dermal damage [12,13]. The prevalence of EPP ranges between 1:75,000 and 1:180,000 in Europe [2,14]. It is more frequent in Japan due to an increased prevalence of the milder variant with a loss of function mutation in the FECH-gene, c.315–48 T > C (present in 43% of Japanese people compared to approximately 10% in the Netherlands) [15]. This variant will only lead to EPP if the patient also has a severe pathogenic mutation in the FECH-gene.
From proteomic landscape to single-cell oncoproteomics
Published in Expert Review of Proteomics, 2021
Vivian Weiwen Xue, Sze Chuen Cesar Wong, William Chi Cho
Nowadays, new single-peptide identification methods such as protein sequencing, nanopore technology, and fluorescent protein fingerprint are emerging to replace MS-based proteomic profiling. By combining these platforms with effective molecular tags, it can realize parallel peptide detection at the zeptomole level [1]. Among them, protein sequencing is a fusion strategy merging Edman degradation with the next-generation sequencing. During sequencing, proteins are fragmented and labeled with fluorescent tags on specific amino acids (AAs). The C-terminal of fragments was immobilized to flow cells. Edman degradation is applied to degrade an AA in each cycle from the N-terminal of fragments, and fluorescence microscopy captures images after each degradation cycle. Although only specific residues with fluorescence labels can be detected, the identified sequence patterns with unknown AAs will be sufficient to match with peptide sequences in databases to identify its parent protein. These sequence blocks with recognized AAs and unknown AAs are also known as peptide fingerprinting [1]. Besides, Ginkel et al. developed a single-peptide identification based on ClpX6P14-mediated protein degradation. ClpX6P14 protein complex is an enzymatic motor that unfolds and degrades proteins. Through immobilizing an array of ClpX6P14 proteases on a PEG-coated surface, ClpX6 subunit recognizes peptides with 11-AA C-terminal ssrA tag and translocate them to ClpP14 for degradation. Fluorescence-labeled AA residues are detected by total internal reflection fluorescence microscopy and alternating laser excitation imaging [32]. Two methods as stated are based on peptide fingerprinting and fluorescence imaging therefore they are limited by imaging accuracy. Differently, aerolysin nanopore-based peptide sequencing aims to realize electrical recognition of single AAs and it was used to successfully identify 13 natural AAs based on the different ionic current patterns in a recent study [2]. This platform is shown to be promising for the direct and de novo sequencing with long reading length in the future.