Although the use of tetracycline antibiotics has diminished over the past years, they continue to be of great importance in the treatment of infectious disease. The broad dissemination of resistance throughout both Gramnegative and Gram-positive populations has had a significant impact on their clinical utility. The glycylcyclines, tetracyclines substituted on position 9 [e.g., GAR-936 (7)(1)], do not appear to be susceptible to the common ribosome protection or efflux resistance (30). Some molecules are in advanced clinical trials for the treatment of drug-resistant infections (31,32).Modified tetracyclines [e.g., 13-cyclo-pentylthio-5-hydroxy-6-deoxytetracycline(8)] have also been shown to block some tetracy-cline efflux pumps such as TetA and TetB, resulting in a reversal of antibiotic resistance (33-35).
Tetracyclines and chemically modified tet-racyclines have been investigated for properties other than their antimicrobial activity (36). For example, tetracyclines are known to have anti-inflammatory properties. These molecules have therefore been pursued as che-motherapeutic agents with promise in the treatment of inflammatory disease such as os-teo- and rheumatoid arthritis. Tetracyclines exert a number of effects related to inflammation. These include the reduction of levels of mRNA encoding NO synthase (37), increasing the levels of cyclooxygenase-2 and subsequent increase in prostaglandin E2 levels (38), and the inhibition of enzymes important to connective tissue biology such as matrix metallo-proteinases (MMPs) and gelatinases. There is a rich literature on the inhibition of MMPs by antimicrobial and chemically modified tetra-cyclines [e.g., CMT-3 (9)] and this property could have application in osteoarthritis (39), periodontitis (40, 41), corneal diseases (42, 43), and cancer (44).
Thus, in addition to the well-established antimicrobial activity of tetracyclines, there are several new therapeutic areas on which
these compounds, or their derivatives, may prove to have a profound impact.
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