Inhibitors of bacterial protein synthesis

Brandi, L., Lazzaroni, A., Cavalletti, L., Abbondi, M., Corti, E., Ciciliato, I., Gastaldo, L., Marazzi, A., Feroggio, M., Maio, A., Colombo, L., Donadio, S., Marinelli, F., Losi, D., Gualerzi, C. O., and Selva, E. (2006c). Novel tetrapeptide inhibitors of bacterial protein synthesis produced by a streptomyces. Biochemistry 43, 3700—3710. 

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. 

Inhibitors are substances that tend to decrease the rate of an enzyme-catalysed reaction. Although some act on the substrate, the discussion here will be restricted to those inhibitors which combine directly with the enzyme. Inhibitors have many uses, not only in the determination of the characteristics of enzymes, but also in aiding research into metabolic pathways where an inhibited enzyme will allow metabolites to build up so that they are present in detectable levels. Another important use is in the control of infection where drugs such as sulphanilamides competitively inhibit the synthesis of tetrahydrofolates which are vitamins essential to the growth of some bacteria. Many antibiotics are inhibitors of bacterial protein synthesis (e.g. tetracyclin) and cell-wall synthesis (e.g. penicillin). 

Berninamycinic acid is one of the products from acid hydrolysis of the cyclic peptide antibiotic berninamycin A, which is a potent inhibitor of bacterial protein synthesis. Berninamycinic acid has been assigned the structure (524), anhydro-3,8-dicarboxy-6-hydroxythiazolo[2,3-/][l,6]naphthyridin-4-ium hydroxide. The 6-hydroxy group arises during hydrolysis from a peptide-bonded amino group (77JA1645). 

Mukhtar TA, Wright GD. Streptogramins, oxazolidinones, and other inhibitors of bacterial protein synthesis. Chem. Rev. 2005 105 529-542. 

Greenwood, D. (1995). Inhibitors of bacterial protein synthesis. In Antimicrobial Chemotherapy, 3rd ed. (D. Greenwood, Ed.), pp. 32-48. Oxford University Press, Oxford. 

Tetracyclines (Table 46-1) are inhibitors of bacterial protein synthesis. 

This inhibitor of bacterial protein synthesis has a narrow spectrum of antibacterial activity. It has been used in the management of abdominal abscess due to Bactewides fragilis, but antibiotic-associated colitis has occurred. 

Kettenring J, Colombo L, Ferrari P, Tavecchia P, Nebuloni M, V ekey K, Gallo GG, Seiva E. Antibiotic GE2Z70 A A novel inhibitor of bacterial protein synthesis. 11. Structure clucida-tiorr. j Antibiot 1991 44 702-715. 

Chloramphenicol acetyl transferase (CAT). This bacterial enzyme was the first reporter protein used for studying the transcriptional activity of eukaryotic regulatory sequences (Gorman et al., 1982). CAT inactivates chloramphenicol, an inhibitor of prokaryotic protein synthesis, by converting it to the mono- or di-acetylated species. Measurement of CAT activity requires a 14C-radiolabeled chloramphenicol or acetyl-CoA and, therefore, an additional step is neccessary to separate the radio-labeled reactant from the product. Novel detection methods based on fluorescent substrates or ELISA assays, which do not use radiolabeled reagents, have been described more recently (Bullock and Gorman, 2000). 

Bacterial infections are treated with antibiotics. There are many antibiotics available, but they fall into three major groups based on their mode of action inhibitors of bacterial nucleic acid synthesis inhibitors of cell wall synthesis and inhibition of bacterial protein synthesis. Resistance of bacteria to commonly-used antibiotics has become a major problem necessitating the development of new antibiotics. Tuberculosis infection is difficult to treat and requires a combination of at least three different antibiotics. 

Developments concerning selectivity, site and mode of action of translation inhibitors have been reviewed repeatedly since a specific inhibition of bacterial protein synthesis was first described in 1950. This study will be concerned mainly with a general view on the problem over the last 25 years and the prospects for future developments. A complete survey of the literature would not be possible in such a brief contribution as this and a number of reviews will be quoted when required. 

Tetracycline one of a class of antibacterials based on a tetracyclic skeleton and that act as a bacterial protein synthesis inhibitors. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

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