Chemistry Reference
In-Depth Information
discovery of microbial natural products-based antibiotics began with the serendip-
itous observation by Fleming in 1929 that bacterial growth was prevented by the
growth of
Penicillium notatum
. Although this discovery was highly publicized
and very important, it took over 10 years before the active material, penicillin,
was purified and structurally elucidated by Florey and Chain in early 1940s. Sub-
sequent commercialization was very quick, driven largely by the medical needs
of World War II. Penicillin was one of the first broad-spectrum antibiotics that
treated bacterial infection and saved millions of lives. Fleming, Florey, and Chain
were awarded the Nobel Prize in 1945 for their efforts on penicillin. The suc-
cess of penicillin led to unparalleled efforts by government, academia, and the
pharmaceutical industry to focus drug-discovery efforts based on the newfound
“microbial” sources for the discovery of natural products beyond plants. How-
ever, initial efforts were mostly focused on the discovery of antibiotic compounds
from fermentations of a variety of microorganisms of not only fungal origin by
also soil-dwelling prokaryotes (e.g.,
Streptomyces
spp.), which led to the discov-
ery by 1962 of almost all novel classes of antibiotic scaffolds that are being used
today. The antibiotic discovery effort was performed largely by Fleming's method
of detection of antibacterial activity on petri plates. Zones of inhibition of bacte-
rial strains on agar plates were measured after applying whole broth or extracts
obtained from microbial ferments (5). As newer biological assays and screening
techniques became available in the 1960s, microbial sources, along with plant and
marine sources, started to be used for screening against other therapeutic targets,
which led to the discovery of leads and drugs in those areas. Examples of these
discoveries will be discussed with the target areas. As time progressed, improved
technologies in biology and chemistry helped with the popularization of natural
products; natural product extracts became part of the screening resource in most
large pharmaceutical houses from 1960 through the 1980s until their de-emphasis
in the early 1990s. Therefore, natural product extracts became popular sources
for the screening against purified enzymes and receptors, an occurrence that led
to the identification of many nonantibiotic natural products that have revolution-
ized the practice of medicine, saved countless human lives, improved quality of
life, and perhaps helped increase life expectancy for humans.
12.2 ANTIBACTERIAL AGENTS
Natural products contribute to over 80% of all antibiotics that are in clinical prac-
tice today. Natural products contribute to all but three classes of antibiotics (3).
Penicillin was the first
β
-lactam and the first broad-spectrum antibiotic dis-
covered that started the “Golden age” (1940-1962) of antibiotics. The structure
of penicillin contains a thiazolidine ring that is fused to a
β
-lactam ring. The
existence and stability of the
β
-lactam ring was highly controversial at the time
despite the availability of a single crystal X-ray structure of one of the peni-
cillins. Penicillin G (
8
) was the first penicillin that was clinically used. Penicillin
