Reducing tetracycline resistance in living cells

Details Reducing tetracycline resistance in living cells Reducing tetracycline resistance in living cells

1994-06-14

1996-12-31

Criares, Theodore J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

3,10-dihydroxy-2-naphthacene carboxamide or derivative doai

A61K 3165

Patent

active

055894704

DESCRIPTION:

BRIEF SUMMARY
RESEARCH REPORT

The research for the present invention was supported by funds obtained through Tufts University.
1. Field of the Invention
The present invention concerns therapeutic tetracycline treatment of living cells, and is particularly directed to methods and materials for altering and overcoming resistance to tetracycline within microorganisms such as bacteria, fungi, rickettsia, and the like.
2. Background of the Invention
The development of the tetracycline antibiotics was the direct result of a systematic screening of soil specimens collected from many parts of the world for evidence of microorganisms capable of producing bacteriocidal and/or bacteriostatic compositions. The first of these novel compounds was introduced in 1948 under the name chlortetracycline. Two years later oxytetracycline became available. The detailed elucidation of the chemical structure of these agents confirmed their similarity and furnished the analytical basis for the production of a third member of this group in 1952, tetracycline. By 1957, a new family of tetracycline compositions characterized chemically by the absence of the ring-attached CH.sub.3 group present in the earlier compositions was prepared and became publicly available in 1959 under the official name demeclocycline. Subsequently, methacycline, a derivative of oxytetracycline, was introduced in 1966; doxycycline became available by 1967; and minocycline was in use by 1972. For clarity, for general ease of understanding, and for comparison purposes, these individual tetracycline type agents are structurally compared within Table I below.


TABLE I ______________________________________ TETRACYCLINE ##STR1## At Carbon Congener Substituent(s) Position Nos. ______________________________________ Chlortetracycline Cl (7) Oxytetracycline OH, H (5) Demeclocycline OH, H; Cl (6; 7) Methacycline OH, H; CH.sub.2 (5; 6) Doxycycline OH, H; CH.sub.3, H (5; 6) Minocycline H, H; N(CH.sub.3).sub.2 (6; 7) ______________________________________
Subsequent to these initial developments, much research effort was focused on developing new-tetracycline antibiotic compositions effective under varying therapeutic conditions and routes of administration; and for developing new tetracycline analogues which might prove to be equal or more effective than the originally introduced tetracycline families beginning in 1948. Representative of such developments are U.S. Pat. Nos. 3,957,980; 3,674,859; 2,980,584; 2,990,331; 3,062,717; 3,557,280; 4,018,889; 4,024,272; 4,126,680; 3,454,697; and 3,165,531. It will be understood that these issued patents are merely representative of the range of diversity of investigations seeking tetracycline and tetracycline analogue compositions which are pharmacologically active.
Historically, soon after their initial development and introduction, the tetracyclines regardless of specific formulation or chemical structure were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. Hence, tetracyclines became known as "broad spectrum" antibiotics. With the subsequent establishment of their in-vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes. However, this widespread use of tetracyclines for both major and minor illnesses and diseases led directly to the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic--as for example pneumococci and Salmonella. The rise of tetracycline-resistant organisms has led not only to a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice, but has also launched major efforts and investigations to uncover the mechanism for tetracycline resistance--in the hope that some effec

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