Resistance protein synthesis inhibitors

Microbial Resistance to Drugs Ribosomal Protein Synthesis Inhibitors... 

Ribosomal Protein Synthesis Inhibitors. Figure 5 Nucleotides at the binding sites of chloramphenicol, erythromycin and clindamycin at the peptidyl transferase center. The nucleotides that are within 4.4 A of the antibiotics chloramphenicol, erythromycin and clindamycin in 50S-antibiotic complexes are indicated with the letters C, E, and L, respectively, on the secondary structure of the peptidyl transferase loop region of 23S rRNA (the sequence shown is that of E. coll). The sites of drug resistance in one or more peptidyl transferase antibiotics due to base changes (solid circles) and lack of modification (solid square) are indicated. Nucleotides that display altered chemical reactivity in the presence of one or more peptidyl transferase antibiotics are boxed. 

Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intramuscularly results in blood levels of 10 mcg/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis. 

The first of a new class of antibiotics (oxazolidinones), linezolid is active against many drug-resistant gram-positive cocci, including strains resistant to beta-lactams and vancomycin (eg, vancomycin-resistant Enterococcus faecium). Linezolid binds to a unique site on the SOS ribosomal subunit, and there is currently no cross-resistance with other protein synthesis inhibitors. Linezolid is available in both oral and parenteral formulations. 

Experimental evidence also supported the hypothesis that the disaccharide analogs inhibit bacterial growth by inhibiting cell wall biosynthesis. They demonstrated bactericidal activity only in actively growing cells, and cells pretreated with protein synthesis inhibitors were resistant to the effects of the disaccharide analogs. In addition, they inhibited incorporation of lysine into cell wall material in intact Ent. faecalis. ... 

Other studies on trichothecenes have shown that the compounds act as potent protein synthesis inhibitors in eukaryotic systems and that they selectively bind to the 60S ribosomal subunit of cells and not to the fungus that produces them (Cundliffe et al., 1974). Thus, resistance shown in Baccharis species may be due to the lack of binding of the trichothecenes to their 603 ribosomal subiinits (Cutler and Jarvis, 1985). Whether a similar mechanism of specific binding sites exist on organelles or cell membranes of susceptible muskmelon genotypes is not known but remains a distinct possibility. The mechanism of cellular activities of the macrocyclic trichothecene, roridin E, on muskmelon plant tissues merits further investigation. 

Chlamydomonas reinhardi is sensitive to the protein synthesis inhibitor, erythromycin. At the time, some erythromycin-resistant strains had been isolated and described, and we were considering experimental approaches to locate the sites of structural genes for proteins of plastid ribosomes. It seemed reasonable to use erythromycin resistance as a genetic marker if we could be certain that the antibiotic interacts with some part of the chloroplast ribosome and was not lethal for some other reason. Erythromycin was known to bind to the large subunit of Escherichia coli ribosomes, and the alteration leading to resistance in the bacteria was found to reside in a single protein in the 50 S subunit. ... 

Inhibitors of protein synthesis 4 The problem of antibiotic resistance... 

Linezohd (Zyvox) is an oxazolidinone, a tive-membered heterocychc ring that forms the core of the hnezohd structure. The approval of hnezohd by the FDA in 2000 marked the first new structural class of antibacterial introduced into medical practice in the United States in 40 years. It is notable for its activity against methicillin-resistant Staph aureus, MRSA, and vancomycin-resistant Enterococcus faecium, VRE. It is bacteriostatic rather than bactericidal but finds significant use in patients with an intact immune system. Like several other classes of antibacterials, linezolid is an inhibitor of protein synthesis. It interacts specifically with the RNA component of a bacterial ribosome subunit to prevent initiation of protein synthesis. 

Mupirocin is not related to any of the sys-temically used antibiotics. It is an inhibitor of bacterial protein synthesis and is especially active against gram-positive aerobic bacteria, e.g. methicillin-resistant S. aureus and group A beta-hemolytic streptococci. Absorption through the skin is minimal. Intranasal application may be associated with irritation of mucous membranes. 

The selection of transformed chloroplasts usually involves the use of an antibiotic resistance marker. Spectinomycin is used most routinely because of the high specificity it displays as a prokaryotic translational inhibitor as well as the relatively low side effects it exerts on plants. The bacterial aminoglycoside 3 -adenyltransferase gene (ciadA) confers resistance to both streptomycin and spectinomycin. The aadA protein catalyzes the covalent transfer of an adenosine monophosphate (AMP) residue from adenosine triphosphate (ATP) to spectinomycin, thereby converting the antibiotic into an inactive form that no longer inhibits protein synthesis for prokaryotic 70S ribosomes that are present in the chloroplast. 

Linezolid Prevents bacterial protein synthesis by binding to the 23S ribosomal RNA of 50S subunit Bacteriostatic activity against susceptible bacteria Infections caused by methicillin-resistant staphylococci and vancomycin-resistant enterococci Oral, IV hepatic clearance (half-life 6 h) dosed twice-daily Toxicity Duration-dependent bone marrow suppression, neuropathy, and optic neuritis serotonin-syndrome may occur when coadministered with other serotonergic drugs (eg, selective serotonin reuptake inhibitors)... 

ACE inhibitors prevent the formation of angiotensin II by angiotensin-converting enzyme (ACE) and thereby reduce peripheral vascular resistance and blood pressure. In addition, ACE inhibitors prevent the effect of angiotensin II on protein synthesis in myocardial and vascular muscle cells, and thus diminish ventricular hypertrophy. As adverse effects, ACE inhibitors may provoke dry cough, impaired renal function, and hyperkalemia. When ACE inhibitors are poorly tolerated, an ATq-receptor antagonist can be given. 

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