Chemistry of Beta Lactam Antibiotics

Humans have been plagued with the threat of bacterial infection since before the dawn of recorded history, and have thus always had a keen interest in finding a suitable treatment for these maladies. In the early part of the 19th century, colonial Americans were fearful of death by bacterial infections that are now considered routine, and usually inquired about one another's health in their letters (indeed, the only casualty during the Lewis and Clark expedition in 1803 was due to a bacterial infection!). Folk medicine is replete with accounts of the use of various materials for the treatment of bacterial infection (moldy bread, moldy cheese, plant and animal preparations), which we now assume were effective due to the presence of some unknown antibacterial agent. The science of microbiology was significantly advanced by Hans Christian Gram, a danish biologist who developed a stain that allowed the facile visualization of some bacteria (now called Gram positive). The ability of certain bacteria to retain this stain lies in the biochemistry of their cell wall. Early researchers such as Koch, Pasteur and Joubert, and Ehrlich demonstrated fundamental properties of bacterial infection, such as the reliable isolation of a single type of organism from a given infection, the absence of such bacteria in normal tissue, and the ability to kill these bacteria with other more common bacteria or organometallics. The modern era of chemotherapy began in 1936 with the discovery of the antibacterial effects of the sulfonamides. Prior to this time, Fleming showed that a contamination of Penicillium mold in a bacterial culture produced a clear zone of inhibition in the culture, and bacteria were killed therein by lysis. Penicillin was not isolated and identified from this source until the early 1940's, and was first employed as an antibiotic agent in 1941. The subsequent discovery of streptomycin from the soil organism Streptomyces griseus (Waksman, 1943), chloramphenicol (1947), chlortetracycline (1948), neomycin (1949) and erythromycin (1951) ushered in the era of the miracle drug. Broad screening programs were then undertaken which identified many of the antibiotic agents in use today. Currently, soil microbes remain the richest source of new antibiotic agents. In 1990, the world consumed literally tons of antibiotics valued in excess of 7 billion dollars; more than half of these antibiotics were of the beta lactam type.