Resistance enzymatic modification

Figure 14 Enzymatic modification of tetracycline. Tetracyclines bind to the ribosome in several areas, but the primary region is in the A site of the small subunit (shown) (A). The antibiotic binds divalent cations such as Mg +, which is essential for ribosome binding. The enzyme TetX catalyzes the mono-hydroxylation of tetracycline at position 11 a disrupting the Mg + binding site resulting in resistance.

Of the effective compodnds available at the present time, the )3-lactam antibiotics, the aminoglycosides and the polymyxins are all bacteriocidal. The j8-lactam antibiotics, notably carbenicillin, suffer primarily from the penetration factor but enzyme activity can play an important part. The aminoglycosides, on the other hand, have few or no penetration problems but are subject to enzymatic modification. The polymyxins penetrate to the active site and appear to be resistant to enzymatic modification. However, toxicity problems associated with polymyxin therapy prevent the widespread use of these drugs. 

Resistance to a range of antibiotics is of increasing concern in clinical practice since the genes are often carried on transmissible plasmids. There are different types of mechanism that confer resistance, inclnding enzymatic covalent modification of the antibiotic, effective efflnx systems, and indnction of a cellnlar enzyme that is resistant to the antibiotic. Examples of these are used as illustration. 

Replacement of the amide by a thioamide bond in peptides represents a minimal modification that may be of interest as it increases resistance against enzymatic degradation. 483,484 Such modification has been reported to both increase14 5 486 and decrease biological activities, and the effect is not readily predictable. 487-489 ... 

Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. 

The enzymatic specificity of diphtheria toxin deserves special comment. The toxin ADP-ribosylates EF-2 in all eukaryotic cells in vitro whether or not they are sensitive to the toxin in vivo, but it does not modify any other protein, including the bacterial counterpart of EF-2. This narrow enzymatic specificity has called attention to an unusual posttranslational derivative of histidine, diphthamide, that occurs in EF-2 at the site of ADP-ribosylation (see fig. 1). Although the unique occurrence of diphthamide in EF-2 explains the specificity of the toxin, it raises questions about the functional significance of this modification in translocation. Interestingly, some mutants of eukaryotic cells selected for toxin resistance lack one of several enzymes necessary for the posttranslational synthesis of diphthamide in EF-2 that is necessary for toxin recognition, but these cells seem perfectly competent in protein synthesis. Thus, the raison d etre of diphthamide, as well as the biological origin of the toxin that modifies it, remains a mystery. 

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