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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.
Introduction to Molecular Biology
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Once the initiation complex is complete, the elongation process begins (Fig. 12), which is carried out by a set of elongation factors. The addition of each new amino acid within the growing polypeptide occurs in three steps: (i) the binding of an aminoacyl-tRNA into the A site of the ribosome, (ii) the formation of a new peptide bond, and (iii) the translocation of the ribosome to the next three nucleotides (next codon) along the mRNA chain. In the first step, the specificity of the tRNA binding is provided by the mRNA codon located on the A site. In other words, the anticodon on the incoming tRNA must pair with the mRNA codon present in the A site. The binding of the tRNA into the ribosome complex requires GTP hydrolysis. After both P site and A site are occupied, the two proximal amino acids are joined together to form a peptide bond by the catalytic activity of an enzyme called peptidyl transferase. This enzymatic activity is situated on the ribosome and no energy is expended at this stage. During this step, the ribosome uses the energy from GTP hydrolysis to move three nucleotides toward the 3′ end of the mRNA. As the ribosome moves, the peptidyl-tRNA present in the A site is translocated in the P site with the aid of translocase enzyme and GTP, while the uncharged tRNA in the P site is translocated to the E site. The A site is now unoccupied and ready for the next tRNA molecule complementary to the mRNA codon. These three steps will be repeated in a cyclic manner during the whole elongation process until the termination happens.
Affinity Modification in Biochemistry, Biology, and Applied Sciences
Published in Dmitri G. Knorre, Valentin V. Vlassov, Affinity Modification of Biopolymers, 1989
Dmitri G. Knorre, Valentin V. Vlassov
These investigations started from the study of the peptidyl-transferase center of ribosomes with tRNA derivatives bearing the reactive group attached to the α-amino group of aminoacyl moiety. The first reagents proposed by three groups of the authors were chlorambucilyl-Phe-tRNA (CXXXIa),273 bromoacetyl-Phe-tRNA (CXXXIb),451 and p-nitrophenoxycarbonyl-Phe-tRNA (CXXXIc).452 The reagents were used to modify E. coli ribosomes within the ternary complex with poly(U) coding for polyphenylalanine. In all three cases, only the 50S subunit was modified, 23S rRNA being attached preferentially by the first two reagents. Interestingly, in the first case a catalytically competent attachment took place; chlorambucilyl-Phe residue covalently attached to 23S rRNA within E. coli ribosomes could participate in a number of subsequent elongation cycles giving rise to chlorambucilyl-oligophenylalanyl-tRNA.453
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.
Streptogramins for the treatment of infections caused by Gram-positive pathogens
Published in Expert Review of Anti-infective Therapy, 2021
Sophie Reissier, Vincent Cattoir
Type A streptogramins block tRNAs attachment to both A and P sites of the peptidyl-transferase center (PTC), and thus preventing the two early steps of elongation (i.e. aminoacyl-tRNA binding to the A site and peptide bond formation with peptidyl-tRNA at the P site) Figure 2 [21,22]. Initially, it was thought that streptogramins A were only able to bind to 50S subunits and free 70S ribosomes and not to ribosomes involved in protein synthesis and polysomes [22]. However, it has been demonstrated that streptogramins A also interact with the entrance of the peptide exit tunnel, and likely bind to translating ribosomes [25]. Type B streptogramins share overlapping binding sites with macrolides and lincosamides (domains II and V of the 23S rRNA), and act similarly by inhibiting translocation, preventing polypeptide extension, and triggering the premature release of incomplete protein chains [21,22]. Streptogramins B binding site is located at the entrance to the ribosome tunnel, and does not contact the PTC Figure 2 [26]. They can interact with ribosomes at any step of protein synthesis, including translating ribosomes and polysomes, inhibiting elongation after a few cycles [22].