Tetracyclines drug resistance

Genes encoding phosphotransferases confer resistance to streptomycin Genes encoding a drug-resistant dihydropteroate synthase enzyme required for folate biosynthesis confer resistance to sulfonamide Tetracycline... 

Use of penicillin and the tetracyclines also causes selection for pathogenicity factors, that is, disease-causing factors. These factors and drug resistance have been shown to be linked on the same plasmid. Pathogenicity and antibiotic resistance can therefore be transferred simultaneously to other organisms. 

Numerous episodes have occurred in which humans have developed drug-resistant nontyphoid Salmonella infections that have been traced to animal sources (23). These bacteria can be transmitted to humans in food or through direct contact with animals. Antimicrobial resistance limits the tlierapeutic options available to veterinarians and physicians for the subset of clinical cases of nontyphoid Salmonella that require treatment. A recent example is a clone of Salmonella typhimurium DT 104 with chromosomally encoded resistance to ampicillin, tetracycline, streptomycin, chloramphenicol and sulfonamides, which has become increasingly common in humans in England and Wales since 1990 (24). Since 1992, only Salmonella enteritidis has accounted for more cases of human salmonellosis than Salmonella typhimurium DT 104 (25, 26). Multiresistant DT 104 has currently emerged in several European countries (27-29) outbreaks have been also reported in the United States in both cattle (30) and humans (31). 

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. 

Acquired bacterial resistance to the tetracyclines has become widespread in animal populations and has severely reduced the usefulness of these drugs. Resistance to the tetracyclines results from plasmid-mediated mechanisms that prevent the active transport of the drug into the bacterial cell or increase the efflux of drug from the bacterial cell. 

The reverse phenomenon, decreased enzyme synthesis, can also be the mechanism of drug resistance. The antimetabolite pro-drug 6-mercaptopurine (6MP) is activated to its nucleotide by inosine-5 -phosphate pyrophosphorylase. The enzyme is deleted in resistant neoplastic cells. Resistance to 5-fluorouracil similarly develops by deletion of the enzyme converting this pro-drug to its active nucleotide. A mechanism of resistance by which a drug is excluded from its site of action can also be operative. This has been established for tetracycline antibiotics. Here the permeability of the cellular membrane to the drug is altered so that it cannot penetrate and accumulate within the target cell. Similarly, it has been demonstrated with such a membrane modification in MTX-resistant leukemia cells in mice. 

Other Bacillary Infections Tetracycline therapy often is ineffective in infections caused by Shigella, Salmonella, or other Enterobacteriaceae because of a high prevalence of drug-resistant strains. Resistance similarly limits usefulness for travelers diarrhea. 

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. 

Esterase formation is a mechanism of macrolide resistance seen in coliforms. Resistance to tetracyclines occurs either from increased activity of efflux mechanisms or changes in cell membrane permeability, leading to decreases in intracellular levels of such drugs. Resistance to chloramphenicol involves plasmid-mediated formation of drug-inactivating acetyltrans-ferases. The answer is (A). 

Decreased drug accuimihition. Tetracycline resistance occurs where the bacterial cell membrane becomes impermeable to the drug or there is increa,sed elllux,... 

Malaria is still one of the most prevalent protozoan diseases in the world. The mosquito infects the human and the parasite passes through two phases. The tissue phase causes no clinical symptoms in the human and the erythrocytic phase invades red blood cells and causes chills, fever, and sweating. In the United States the 1000 cases reported annually are almost all from international travel. Quinine was the only antimalarial drug from 1820 to the early 1940s when synthetic antimalarial drugs were developed. Chloroquine is commonly prescribed. If drug resistance develops quinine is used in combination with an antibiotic such as tetracycline. 

---