In 1945, after
penicillin had been introduced into medicine, an
antibiotic-producing species of Cephalosporium was isolated from a sewage outfall in Sardinia. Four years later in Oxford, this organism was found to produce several
antibiotics, one of which was a
penicillin with a new side-chain,
penicillin N. During a chemical study in 1953, this
penicillin was shown to be contaminated with a second substance,
cephalosporin C, which contained a
beta-lactam ring but was resistant to hydrolysis by a
penicillinase (
beta-lactamase). At that time,
penicillinase-producing Staphylococci were causing a serious problem in hospitals. The isolation of the nucleus of
cephalosporin C (7-ACA) enabled
pharmaceutical manufacturers to produce many thousands of
cephalosporins, some of which have been effective in the treatment of serious
infections by a number of Gram-positive and Gram-negative bacteria. The
cephalosporins, like the newer
penicillins, have a very low toxicity and have greatly extended the range of
chemotherapy. New, sensitive screening methods have revealed further families of clinically useful substances that contain a reactive
beta-lactam ring. Genetic engineering has now begun to throw light on the nature of the
enzymes that are involved in the biosynthesis of
penicillins and
cephalosporins, and x-ray crystallography may soon provide detailed 3-dimensional pictures of some of the bacterial
enzymes with which the active
beta-lactam ring reacts. Rational approaches to the production and design of new and potentially useful compounds may then be within sight.