Drug discovery tetracyclines

Here as with the tetracyclines, the solution of difficult chemical problems was a prerequisite to successful new drug discovery. At first the counterpart of 6-aminopenicillanic acid could be made only in very low yields by chemical hydrolysis. A practical enzymatic hydrolysis of cephalosporin C to 7-aminocephalosporanic acid (7-ACA) was not found. R. B. Morin and co-workers provided the elegant solution (Figure 21) (101), which made the preparation of 7-ACA and semisynthetic cephalosporins possible on a practical scale. The impetus to persevere in this... 

Discovery of Kanamycin, and Establishment oflMC. Chloramphenicol, chlor- and oxy-tetracyclines, and pyridomycin (H. Umezawa, 1967) were active, in in vitro experiments, against strains of tuberculosis, but these drugs, in contrast to streptomycin, were clinically inactive. H. Umezawa... 

The discovery of a novel structural class of antibacterials is notable, as these are few and far between. The sulfa drugs, p-lactams, quinohnes, tetracyclines, macrohdes, and aminoglycosides have been around for decades. Multiple improvements have been made over time in each of these classes but without breaking out into new structural classes. There are two notable, recent examples of new stractural classes of antibacterials and these are worth knowing about. 

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). 

Robinson expressed this skepticism (45) when he wrote in 1953 .. . indeed one of the disappointments in antibiotic work is that it seems impossible to modify the molecule without reducing or eliminating its antimicrobial activity. . . The discoveries early in the 1950 s of tetracycline and phenoxymethylpenicillin established beyond doubt, however, that modification of antibiotics by chemical or biosynthetic means could yield superior drugs. 

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