Tetracyclines resistance mechanisms

Tigecycline IV unaffected by common tetracycline resistance mechanisms very broad spectrum of activity against grampositive, gram-negative, and anaerobic bacteria nausea and vomiting are the primary toxicities... 

Hillen W, Berens C (1994) Mechanisms underlying expression of TnlO encoded tetracycline resistance. Annu Rev Microbiol 48 345-369... 

R-plasmid-mediated resistance is almost invariably associated with crossresistance to a number of related and unrelated antibiotics. The reasons for the association lie in the resistance mechanism to related compounds that have been coded, the usual presence of more than one R determinant in the same plasmid, and the frequent coexistence of several different plasmids in the same bacterial cell. As a result, use of any antibiotic can lead to development of resistance to itself and to other related and unrelated antibiotics. If, for example, a plasmid is encoded for resistance to ampicillin, tetracycline, sulfonamide, and streptomycin, exposure to any of these antibiotics results in resistance to all the others, whereas the use of a -lactamase-containing strain results in resistance to other members of this group. 

Following this line of work, we made the discoveries reported here. Before we indicate these, we note that the microarray datasets that we analyzed for tetracycline and chloroquine do not contain many differentially regulated reactions. The possibility remains that studying drug resistance mechanisms of the malaria parasites at the transcriptional level of their proteins is not reliable (Karine Le Roch, personal communication). 

With the first in silico model, we were able to use the biochemical network of P.falciparumto deduce its drug resistance mechanism(s) using two sets of gene expression data obtained from treatment of the parasite with chloroquine and tetracycline. Our work is the first to develop and apply computational means toward the elucidation of these mechanisms in P. falciparum. Our work suggests viable mechanisms for the resistance of the malaria parasite to chloroquine and tetracycline. When these results are experimentally tested they may provide useful weapons to efficiently cleanse malaria parasites from the blood stream. 

The resistance mechanisms that cause the inactivation of penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not apply to fluoroquinolones, and there is therefore no cross-resistance between quinolones and other antibiotics. 

Connell SR, Tracz DM, Nierhaus KH, Taylor DE. Ribosomal protection proteins and their mechanism of tetracycline resistance. Antimicrob. Agents Chemother. 2003 47(12) 3675-3681. 

Sykes and Richmond [151] reported on strains of Ps. aeruginosa carrying extrachromosomal resistance to tetracycline which can be transferred to other strains of Ps. aeruginosa and strains of E. coli. The R factor carrying pseudomonas strains showed a 100-fold increase in resistance to tetracycline over the R strain. However, the resistance mechanism was not investigated. 

Fig. 13.6 Structural modifications at the 9 position of the tetracycline antibiotic minocycline conferring increased stability against resistance mechanisms.

Resistance is widespread and often is indncible. The three main resistance mechanisms are (1) decreased accumulation of tetracycline (decreased antibiotic influx or acquisition of an energy-dependent efflux pathway) (2) production of a ribosomal protein that displaces tetracycline from its target, a protection that also may occur by mutation and (3) enzymatic inactivation of tetracyclines. Cross-resistance amongst tetracyclines depends on which mechanism is operative. Tetracycline resistance due to a ribosomal protection mechanism produces cross-resistance to doxycycUne and minocycline because the target site protected is the same for all tetracyclines. 

Plasmid-mediated resistance to tetracyclines is widespread. Tetracycline-resistant organisms show decreased intracellular accumulation of the drugs. Resistance mechanisms include decreased activity of the uptake systems and the development of mechanisms (efflux pumps) for active extrusion of tetracyclines. Plasmids that include genes involved in the production of efflux pumps for tetracyclines commonly include resistance genes for multiple antibiotics. 

Like all tetracyclines, the glycylglycines act at the bacterial ribosome to arrest trans iation (60). Their utility against Eetracycline tesistant bacteria is due to their ability to circumvent the two main resistance mechanisms. The glycylglycines bind the ribosome... 

Roberts MC- Tetracycline resistance determinants—mechanisms of action, regulation of expression, genetic mobility, and distribution. FEMS Microbiol Rev 1996 19 1-24-... 

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