Tetracycline resistance

MECHANISM OF ACTION AND RESISTANCE Tetracyclines inhibit bacterial protein synthesis by binding to the 30S bacterial ribosome and preventing access of aminoacyl tRNAto the acceptor (A) site on the mRNA-ribosome complex (Figure 46-1). They enter gram-negative bacteria by passive diffusion through channels formed by porins in the onter ceU membrane and by active transport that pumps tetracyclines across the cytoplasmic membrane. 

The total U.S. antibiotic market for 1990 was about 4.73 biUion, 233 million of that was tetracyclines. The development of the semisynthetic P-lactam antibiotics (see Antibiotics, P-LACTAMs) and emergence of resistance to the tetracyclines has steadily diminished the clinical usefulness of tetracyclines. 

Fig. 4. Comparison of the three types of tetracycline resistance where T represents the tetracycline molecule O, a tetracycline transporter and aaa/, the ribosome A shows the effect of tetracycline exposure on a sensitive cell B, the efflux of resistance where a cytoplasmic membrane protein ( D) pumps tetracycline out of the cell as fast as the tetracycline transporter takes it up C, the ribosomal protection type of resistance where the ribosome is modified by ( ) to block productive binding and D, the tetracycline modification type of resistance where t is an inactive form of tetracycline. Reproduced with...

Resistance to Tetracyclines. The tetracyclines stiU provide inexpensive and effective treatment for several microbial infections, but the emergence of acquired resistance to this class of antibiotic has limited their clinical usehilness. Studies to define the molecular basis of resistance are underway so that derivatives having improved antibacterial spectra and less susceptibiUty to bacterial resistance may be developed. Tetracyclines are antibiotics of choice for relatively few human infections encountered in daily clinical practice (104), largely as a result of the emergence of acquired tetracycline-resistance among clinically important bacteria (88,105,106). Acquired resistance occurs when resistant strains emerge from previously sensitive bacterial populations by acquisition of resistance genes which usually reside in plasmids and/or transposons (88,106,107). Furthermore, resistance deterrninants contained in transposons spread to, and become estabUshed in, diverse bacterial species (106). 

Table 2. Classification and Distribution of Tetracycline Resistance Determinants in Microorganisms ...

Glycylcyclines are a new generation of tetracyclines (e.g. tigilcycline), which have been developed to overcome problems of resistance to common tetracyclines. 

Resistance to tetracyclines is often caused by the acquisition of genes (e.g. tetO and tetM) coding for so-called ribosome protection proteins. These proteins bind to the ribosome and protect them from tetracycline action. 

The tetracyclines are important antibiotics often effective against organisms showing penicillin resistance. In 1980, a synthesis of some sulphur containing tetracyclines ° required thiol (14) as an intermediate. The SH group could be introduced by nucleophilic displacement of a diazonium salt (guideline 4) so amine (IS) is an essential intermediate. 

Thiatetracyclines contain a sulphur atom at position 6 in the molecule. One derivative, thiacycline, is more active than minocycline against tetracycline-resistant bacteria. Despite toxicity problems affecting its possible clinical use, thiacycline could be the starting point in the development of a new range of important tetracycline-type antibiotics. 

The tetracyclines are no longer used clinically to the same extent as they were in the past because of the increase in bacterial resistance. 

A more recently recognized mechanism of dmg resistance is that of efflux in which the antibiotic is rapidly extmded horn the cell by an energy-dependent mechanism. This affects antibiotics such as the tetracyclines and macrolides. 

Plasmid- or transposon-encoded ribosomal protection factors are a second mechanism of resistance to the tetracyclines. These proteins are believed to alter the tetracycline binding site on the 308 ribosomal subunit, lowering the affinity for the drugs. 

OmpF mutations in Gram-negative bacteria such as E. coli (see above) can result in low level resistance to the tetracyclines by reducing their uptake. 

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