Overview of Penicillin
The onset of advancements in drug discovery in the 20th century influenced the
invention and production of key antibiotics. Penicillin was one of the many significant
antibiotics chemicals, which can kill or stop the growth of disease, to be discovered by
Alexander Fleming during this period. The advent of penicillin reduced “deaths by
infectious diseases to only one-twentieth” of what they were estimated as in 1900s (Fogel).
Penicillin was soon known as a universal drug or “wonder drug” from its biological and
organic properties that resulted in apoptosis of bacterial cells and the derivatives created
that would further increase its potency.
Penicillin was established as the “wonder drug” in the pharmaceutical industry by
its efficacy and potency in treating bacterial infections and reproduction. Penicillin was
discovered by Alexander Fleming in 1929 from the isolation of a mold, Penicillium notatum.
(Penicillum is a genus of over 300 species of mold. Multiple species can produce multiple
strains. Might be worth mentioning.)Neighboring cell plates of the mold’s secretion showed
diminishing cell growth, indicating to Fleming of Penicillin’s unique ability. Fungal colonies
streaked onto plates containing bacterium Staphylococcus aureus, exhibited transparent
colonies due to the lysing of the bacterium’s cell walls (Discovery and Development of
Penicillin). The effects of Penicillin were evident in its ability to prevent bacterial cell
growth in their reproductive phase, mitosis. The potency of Penicillin instantaneously
sparked further research into the fungal metabolite in its ability to control bacteria.
Although Fleming was the initial scientist to discover Penicillin, he was unable to purify the
compound for commercial use due to its instability. Commercial production of the
Penicillin would not be possible until the work of Howard Florey, Ernst Chain, and Norman
Heatley at Oxford University during 1938. Florey and Chain focused upon improving
purification methods and their efficiency by incorporating various types of mold. Of these,
P. chyrsogenumby was discovered by Mary Hunt which revolutionized Penicillin production
in the drug industry. In comparison to Penicillium notatum, P. chyrsogenumby doubled
penicillin growth in the drug industry (Development and Discovery of Penicillin). Florey
and Chain further enhanced Penicillin production through the use of corn steep liquor
which significantly increased the yield of Penicillin. Their research in Penicillin’s “growth,
extraction, and purification” allowed for distribution on an industrial scale or widespread
use (Fogel). Penicillin quickly became a valuable drug in the pharmaceutical industry in its
high activity rate in bacterial control and low toxicity to the human body.
The unique biological properties of Penicillin allow for the inhibition of bacterial
growth by preventing the formation of new cell walls. Specifically, the cross-linkage of
small peptide chains in peptidoglycan are prevented, causing the lack of cell wall polymers
in bacteria. The beta-lactam ring of Penicillin irreversibly binds to an enzyme active site on
the bacterial cell. From this, the attempt at developing a new cell wall during mitosis is
prohibited (Shodor). The lack of a cell wall in resulting daughter cells “makes them more
susceptible to osmatic lysis.” Furthermore, the bacterial cells are forced to grow at a larger
size, reducing the frequency of cell division (Penicillin and Other Antibiotics). Although
Penicillin is effective in preventing further bacterial cell growth, it is limited to affecting
only newly produced cells and not pre-existing bacterial cells. Clearly, the biological
properties of Penicillin allow for it to become a universal drug in bacterial treatment.
In addition to Penicillin’s distinctive biological properties were its organic
properties. Its organic structure was deduced to be of a beta-lactam derived from valine
and cysteine with a tripeptide intermediate replaced with an acyl group (Shodor). The
organic structure exhibited a close relation to variations of Penicillin through the natural
occurrence of Penicillin G and Penicillin V. Their differing chemical structures allow for
varying properties in which Penicillin V is much more effective in acidic environments in
comparison to Penicillin G. Both however, are only effective in the prevention of bacterial
growth in Gram-positive bacteria, those with a cell wall that consists of thick layers of
peptidoglycan. Ideally, Penicillin G and Penicillin V were used for treating pathogens that
invaded the human body via wounds (Penicillin and Other Antibiotics). The restrictions of
Penicillin G and Penicillin V called for the synthesis of new variations that could be
effectively applied to certain environments thus leading to the development of semisynthetic penicillin. The natural versions were modified by “removing the acyl from 6aminopenicillanic acid,” allowing for the addition of various acyl groups with specific
properties. From this, varying types of Penicillin were deduced such as Ampicillin,
Carbenicillin, and Oxacillin. Each had their unique properties where they were “resistant to
stomach acid, resistant to penicillinase, and possess extended range of activity against
Gram-negative bacteria,” respectively. Evidently, the chemical structure of Penicillin
allowed for it to rapidly become the universal drug due to itsversatility in the drug
industry.
Within recent years bacterial resistance to penicillin has become more common.
Penicillin usually falls into two categories, Biosynthetic and semi-synthetic. Biosynthetic is
natural penicillin that is harvested from mold through fermentation, while semi-synthetic
penicillin are chemically modified derivatives allow the drug to have new properties.
Penicillinase is the enzyme within bacteria that has evolved to destroy penicillin. Bacteria
that contain the penicillinase compound have a resistance to penicillin. The most common
name for this group of enzymes that are produced by bacteria is Beta-lactamase. Betalactamases provide resistance against anti-biotics due to their ability to break down the
structure of the anti-biotic. This enzyme uses the mechanism of hydrolysis; the enzyme
breaks the beta-lactam ring open which deactivates the molecular antibacterial property..
Due to this reason it is very important that penicillin is used with utmost care, due to the
fact that there may be bacterial resistance to this drug. Due to this family of enzymes, betalactamases, new derivatives of penicillin were developed, such as cephamycins and
carbapenems.
Within this group of beta-lactam antibiotics, carbapenems have the highest
resistance to most beta-lactamases. This is due to the carbapenem structure. From its
structure, carbapenems have a similar 5 carbon ring feature as its parent compound,
penicillin, with an additional unsaturated bond between C2 and C3 and a substitution of
carbon at C1 for sulfur. The replacement of carbon 1 with sulfur helps contribute in the
potency and spectrum of the compound against β- lactamases bacteria with higher
stability. Furthermore, its stereochemistry of a trans configuration at C5 and a R chirality
center at C8 increase its antimicrobial spectrum, which corresponds to higher resistance to
hydrolysis by the β- lactamases. In term of origin, Carbapenem was developed from
carbapenem thienamycin. Carbapenem thienamycin was first discovered in 1976 through
streptomyces. Stretomyces are a family of bacteria belonging to the streptomycetaceae
family. Thienamycin is the most potent naturally produced anti-biotic. This is an excellent
drug against both gram positive and negative bacteria and is resistant to Beta-lactamases
enzymes. Unlike penicillin, thienamycin is a naturally occurring antibiotic that has
resistance to beta-lactamases. One important substituent of the two structures,
carbapenem and thienamycin, that cause relatively high resistance to hydrolysis of most βlactamases is the hydroxyethyl side chain of thienamycin. The side chain has an acyl amino
substituent on the β- lactam ring, which provides potent antibacterial and inhibitory
activity. Although these two β- lactamases inhibitors provide the? greatest potency against
the bacteria, more resistant bacteria, such as multidrug-resistant pathogens, are emerging.
Due to the vast library of bacteria that has been discovered to have anti-biotic resistance,
more and more drugs have to be discovered that are capable of destroying bacteria.
Carpaenems, which have the broadest spectrum of activity against gram-positive
and negative bacteria, are used to treat complicated bacterial infections in clinical uses.
This penicillin β group is combined with an antibiotic, which targets gram- positive if use to
treat severe hospital-acquired infection as empirical treatment. The antibiotics contain
groups of compounds that vary in the types of treatment for patients, which include
“antipseudomonal, anti-methicillin-resistant S. aureus (MRSA) carbapenems (i.e., cationic
and dithiocarbamate carbapenems), orally available carbapenems, trinem carbapenems,
and a dual quinolonyl-carbapenem (Antimicrob. Agents Chemother. November 2011 vol.
55 no. 11 4943-4960)”. Interestingly, the first oral carpaenems invented was Tebipenempivoxil, which increased the intestinal absorption for patients, particularly children with
pneumonia illness. Although Carpaenems are beneficial, careful care prescribed from
doctors should be considered to heal the necessary infections.
With today’s modern technology and need for medication, anti-biotics are not
developed on a micro but amacro scale. Industrial production of penicillin and also other
beta-lactam antibiotics are very tedious tasks that require constant monitoring. Most of
these antibiotics require fermentation.. The concepts to consider within industrial
fermenters are functionality and economics. Within the economic aspect the fermenter has
to be easy to “operate, flexible, low power consumption, stable, cheap”. The functional
aspects of the fermenter have these following characteristics: a “high gas/liquid mass
transfer, reasonable heat transfer aggregation prevention, bulk flow, and nutrient transfer”.
Mass transfer is a very important aspect of the fermenter because it facilitates the flow of
oxygen within the tank. Oxygen is very important because mold is an aerobic organism;
therefore, it is important to have a good flow of oxygen between molds and liquid. Heat
transfer is very important because metabolism is an exothermic process. Therefore, there
have to be systems that cool the reactor. There also has to be a continuous culture that
allows liquid to be added in and simultaneously released. Along with this there are special
conditions for penicillin; most penicillin’s require a pH of 6.5 for growth, this is mostly
maintained by the addition of sodium hydroxide (NaOH). These are the optimum
conditions for facilitating the production of penicillin.
The rapid growth of Penicillin in the early 20th century has been exhibited in its
ability to treat bacterial infections and its versatility. Its discovery and growth as a drug
enabled for the advancement in medicine and drug discovery in which previous ailments
have an easily identifiable cure. Its efficacy influenced the development of new antibiotics
while remaining as a front-line antibiotic. Ultimately, Penicillin can be regarded as the
universal or wonder drug to a significant extent due to its versatility and potency in the
medicinal environment.