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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
Linezolid (LZD) is a water-soluble acid (log P 0.64, pKa −0.66–14.45, MW 337.35). It is a synthetic inhibitor of ribosomal translation which binds to the 23S subunit preventing binding of formyl-methionine tRNA and therefore formation of the initiation complex.201 Wild-type MIC99s for LZD range from 0.125 to 0.5 μg/mL.85 Resistance is associated in vitro with point mutations in the peptidyl transferase domain of the 23S rRna (rrs gene), particularly G2576T and in the gene rplC which codes for the L3 protein within the 50S subunit. The latter appears to be more clinically relevant.202
Trichothecenes
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
I. Malbrán, C.A. Mourelos, J.R. Girotti, G.A. Lori
Trichothecenes act as translational inhibitors, suppress the defense response in host plants, and keep the plant from sealing the diseased tissue.32,33 These metabolites bind to the 60S ribosomal subunit, inhibit peptidyltransferase activity, which is required for polypeptide elongation and termination, and, as a result, inhibit protein synthesis.26–31 Furthermore, evidence suggests that trichothecenes can affect the electron transport system, membrane integrity, leaf chlorophyll content, and other functions of plant tissues.1 The T-2 toxin, synthesized mainly by F. sporotrichioides, inhibits protein synthesis and mitochondrial electron transport, and also affects cell membrane function by disrupting the transport of amino acids, nucleotides, and glucose, and the activity of the Ca-K channel.40–42
Mechanisms of action
Published in Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani, Pharmacology in 7 Days for Medical Students, 2018
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani
It is bacteriostatic for all susceptible microorganisms by protein synthesis inhibition at ribosomal level by binding reversibly to 50S ribosomal subunit near the binding site for macrolides and clindamycin (thus these drugs can interfere with each others actions). Chloramphenicol inhibits binding of amino acids containing aminoacyl tRNA to the acceptor site of the mRNA-ribosomal complex. Interaction between peptidyl transferase and its amino acid substrate is prevented. Amino acids are not added to the growing peptide chain so protein synthesis is inhibited.
Linezolid-related adverse effects in the treatment of rifampicin resistant tuberculosis: a retrospective study
Published in Journal of Chemotherapy, 2023
Dan Cui, Xiaomeng Hu, Li Shi, Dongchang Wang, Gang Chen
The continuous increase of DR-TB urgently requires new treatment strategies and new anti-tuberculosis drugs. Recent studies found that linezolid (LZD), as one of the second-line core anti-tuberculosis drugs recommended by the WHO, exhibited good anti-tuberculosis activity [11,12]. The active ingredients of LZD could efficiently distributed into various tissues, including lungs and cerebrospinal fluid [13]. The mechanism study of LZD showed that it mainly binds to the 23S site of the Peptidyl-transferase center (PTC) on the 50S ribosome. This hinders the formation of 70S initiating complex, and effectively disrupts the production of bacterial proteins, which results in TB death [14]. Particularly, LZD can inhibit the production of TB protein at the sites which are different from other anti-tuberculosis drugs [15]. Therefore, treatment with LZD would be difficulty to produce natural drug resistance. The previous studies demonstrated that LZD has an anti-Mycobacterium tuberculosis effect both in vitro and in vivo [16]. Moreover, multiple clinical trials also have confirmed the drug tolerance and efficacy of LZD for drug-resistant TB [17]. However, there is still little evidence regarding the safety of LZD in the long-term treatment of DR-TB in China.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
Similarly, oxazolidinone-based antibiotics are known to bind to the peptidyltransferase center (PTC) of the 50S ribosomal subunit, preventing the formation of the initiation complex itself, thus resulting in inhibition of protein synthesis [36]. Oxazolidinone-based antibiotics are characterized by a core structure consisting of an oxazolidone ring with the S configuration of the substituent at C5, linked to an acylaminomethyl group and an N-aryl substituent [37]. The 50S ribosomal subunit is composed of 5S rRNA, the 23S rRNA, and structural proteins. Despite binding to rRNA in the ribosomal complex, the mechanism of action of oxazolidinone-based antibiotics differs greatly from aminoglycoside-based antibiotics and does not affect peptidyl elongation nor translational termination. Oxazolidinone-based antibiotics crosslink the 23S rRNA with other structural ribosomal proteins, binding to the universally conserved U2585 rRNA nucleotide, thereby stabilizing the base in an orientation that induces a nonproductive conformation of the PTC. Importantly, other RNA structures have been shown to efficiently bind to oxazolidinone derivatives and analogs. For instance, oxazolidinone analogs have been shown to bind to the non-ribosomal RNA T-box antiterminator, a key component of the T-box riboswitch [38] responsible for regulating RNA transcription in response to metabolic effector molecules in Gram-positive bacteria.
Deoxynivalenol and its modified forms: key enzymes, inter-individual and interspecies differences in metabolism
Published in Drug Metabolism Reviews, 2022
Yating Wang, Jiefeng Li, Xu Wang, Wenda Wu, Eugenie Nepovimova, Qinghua Wu, Kamil Kuca
Deoxynivalenol (DON) (Figure 1) is primarily produced by Fusarium graminearum and F. culmorum contaminating food crops, such as wheat, barley, and corn (Khan et al. 2020). DON can exist in the environment and food chain for a long time, posing a serious threat to the health of animals and humans, causing huge economic losses to the global food industry (Goncalves et al. 2020; Zhao et al. 2021). Additionally, DON has various toxic effects in humans and animals, including immunotoxicity, intestinal toxicity, and neurotoxicity (Zhang et al. 2020b; You et al. 2021). At the molecular level, DON binds to the A-site of the peptidyl transferase center (PTC) of the ribosome (de Loubresse et al. 2014). This binding inhibits protein synthesis, induces ribotoxic stress, and leads to the activation of protein kinase R (PKR) and several mitogen-activated protein kinase (MAPK) pathways (Wu et al. 2017). Therefore, effectively controlling DON in food and feed and reducing its harmful effects on animals are necessary means for the healthy breeding of livestock and poultry and ensuring food safety.