Biosynthesis of beta Lactam Antibiotics

 BIOSYNTHESIS OF β-LACTAM ANTIBIOTICS

Alexander Fleming discovered the mold that makes penicillin in the 1920s. The story is a classic case of chance favoring the prepared mind. Fleming left Petri dishes containing bacterial cultures lying around long enough to get moldy. He then noticed a clear zone, in which the bacteria had been killed and had disintegrated, around a blue mold of the Penicillium group. He found that the mold excreted a chemical toxic to bacteria but harmless to animals—penicillin. Fleming called the mold Penicillium notatum. A related mold, Penicillium chrysogenum, makes a related antibiotic called cephalosporin C. Both antibiotics are members of the b-lactam family and are made by separate branches of the same biosynthetic pathway (Fig. 13.18).

The original β-lactams made by molds can be altered chemically to give many different antibiotics. Although cephalosporin C itself has only feeble antibacterial activity, it is the starting point for a vast array of broad-spectrum antibiotics made by chemical modification. First, cephalosporin C must be converted to 7-ACA (7- aminocephalosporanic acid), which is not made by any known organism.

Originally this step was done chemically and gave very low yields. Recently, a mold that makes cephalosporin C was engineered to convert this to 7-ACA.

Two extra genes were inserted to create the extended pathway (Fig. 13.19). The gene for D-amino-acid oxidase was taken from a fungus (Fusarium solani) and the cephalosporin acylase gene from a bacterium (Pseudomonas diminuta).

The 7-ACA is used as base compound for a massive range of chemical modifications that provide antibiotics with different properties. Among these are variants that are resistant to bacterial β-lactamases and others that penetrate bacterial cell walls better as well as antibiotics with better pharmacological properties (e.g., superior absorption from the intestine).