Anti-Infectives from Nature - Natural Products Chemistry: Sources, Separations, and Structures - page 89

9 Anti- Infectives

from Nature

9.1 ANTIMICROBIAL β - LACTAMS
There are many ß-lactam antibiotics. They are characterized by a four-membered
ß-lactam ring (Figure 9.1). Examples include penicillins, cephalosporins, clavams
(or oxapenams), cephamycins and carbapenems, monobactams, and nocardicins;
almost all derived initially from microbes through a fermentation process.
Penicillin G (Figure 9.2) was the first β-lactam antibiotic that entered the clinic.
It has a bicyclic structure consisting of a four-member β-lactam ring and a five-
member hydrothiazole ring. The activity of these antibiotics is related to the opening
of the ß-lactam ring. A large ring strain leads to both its high antibacterial potency
and its instability under acidic and basic conditions.

HISTORICAL NOTE

In 1928, the UK microbiologist Alexander Fleming made the “accidental”
discovery that a metabolite produced by the strain of blue-green mold could
resist the Staphylococcus aureus bacterium. He did not pursue this work fur-
ther. In 1938, Howard Florey and Ernst Chain began work on the extraction of
penicillin from fermented broth, followed in the 1940s by purification of large
amounts of penicillin from a strain of Penicillium notatum . However, peni-
cillin is acid labile and resulted in low yields. The scientist Norman Heatley
developed a back extraction method by controlling the pH of the broth and
using a higher producing strain, Penicillium chrysogenum . In this manner over
200 times more penicillin was produced by P. chrysogenum than P. notatum .
The power of coupling microbiology, strain development, and fermentation
technology took on an altogether major step during World War II (1939-1945).
The significance and importance was not lost on the allied governments, as
large numbers of soldiers were dying from secondary infections in combat.
Thus, the demand for a large amount of penicillin to be produced saved the lives
of soldiers who otherwise would have died due to infection of their wounds.
Yet remarkably, although prescribed to humans, the structure and purity of
penicillin was not fully determined until after the war, a situation that today
would not be acceptable to regulatory bodies such as the U.S. Food and Drug
Administration (FDA).
Today, modern forms of penicillin are the frontline antibiotics to counter
infections, caused by gram positive and gram negative bacteria, and attack
diseases such as pneumonia and gonorrhea.

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