The penicillins are produced by the molds Penicillium notatumandP. chrysogenum.
Through the use of different culture media or biosynthetic precursors (e.g., phenylacetic
acid), a number of biosynthetic (“natural”) penicillins have been isolated, frequently
distinguished by Roman numerals in the United Kingdom and by letters in the United
States. The most important and still used among these is benzylpenicillin or penicillin G,
a singularly nontoxic compound highly active against Gram-positive infections such as
staphylococcal sepsis, meningitis, and gonorrhea.
Structurally, the β-lactam ring fused with the thiazolidine ring is most unusual, since
β-lactam rings were unknown before the discovery of penicillin. Consequently, the elu-
cidation of the structure of penicillin during World War II, a top-secret joint Anglo-
American project, was a difficult undertaking, ultimately settled by X-ray crystallography.
The penam ring can be considered as a dipeptide composed of a cysteine and a valine
residue.
Owing to the strain of the four-membered β-lactam, the ring is easily cleaved by acid
hydrolysis and alcoholysis, and by heavy metals such as Zn^2 +,Cu^2 +, and Pb^2 +. The
resulting penicilloic acid is inactive and undergoes a complex series of rearrange-
ments. The acid sensitivity of penicillins varies with their structure. For example, phe-
noxymethyl penicillin is more resistant to acid cleavage than benzylpenicillin, and is
therefore more suitable for oral use. Even so, considerably higher peroral doses are
required than parenteral ones. Only among the semisynthetic penicillins does one find
good acid resistance. The high reactivity of the β-lactam ring is the key to the biologi-
cal activity of the β-lactam antibiotics. It acts as an irreversible inhibitor of the bacter-
ial transpepticlase because it acylates the enzyme protein near the active site through
opening of the lactam ring (see figure 9.4).
EXOGENOUS PATHOGENS AND TOXINS 565Figure 9.4 Mechanism of penicillin. By means of its highly reactive lactam ring, penicillin
is able to deactivate the transpeptidase enzyme. This in turn leads to a halting of cell wall
construction within the bacterium, ultimately leading to bacterial death.