Directional Regions The core structure of all clinically useful tetracyclines features conserved areas in the “east” and “south” regions of the molecule (see below), the areas known to participate in binding to the bacterial ribosomal target. | 
“Directional” regions of the tetracycline core molecule,
with substitution positions numbered 1-12. |
Evolution of Tetracycline antibiotics over 60 years The tetracycline class of antibiotics comprise a distinct family of substituted hydronaphthacene compounds produced by strains of Streptomyces bacteria. The first member of the group to be discovered was chlorotetracycline (Aureomycin) in the late 1940s by Dr. Benjamin Duggar, a scientist employed by Lederle Laboratories, who derived the substance from a soil-dwelling bacterium named Streptomyces aureofaciens. Two years later, Finlay and coworkers reported the isolation of terramycin produced by Streptomyces rimosus. Nobel laureate Robert B. Woodward determined the structure of oxytetracycline enabling Pfizer chemists, led by Lloyd H. Conover, to successfully produce tetracycline itself as a synthetic product.
Few new antibiotics have been developed and approved in recent years. In June 2005, Tigecycline was introduced to treat infections which are resistant to other antimicrobials. The last version of a tetracycline analog, before Tigecycline, was approved in 1973. |
To date, chemically modified tetracycline analogs have invariably been prepared by semisynthesis, or chemical transformation of isolated natural products. Until now, this approach has greatly limited the range of accessible structures that might be studied as new antibiotic candidates.The Tetraphase platform allows us to build these polyfunctional molecules with previously unaccessible structural variability, going beyond the limitations of current chemical synthesis methods to build diverse, potent and novel compounds. |
