Discovery of penicillin medicine has been a significant effort in medicine world. Penicillin was fully introduced in the 1940s and opened the door for the era of antibiotics. Historically, this invention is recognized as one of the significant developments in therapeutic medicine in the United Kingdom. After its introduction, various studies were conducted regarding its effectiveness and ways of starting mass production of penicillin worldwide. The United States became the first country to engage in large-scale penicillin production before second world war and became live-saving medicine (Bentley, 2005, p.444-452). The paper aims at analyzing the history of penicillin from its invention, improvements and upscaling, and subsequent developments of penicillin medicine.
Alexander Flemings Discovery of Penicillin
Penicillin was discovered by Alexander Fleming in 1928. Alexander suggested that penicillium mold must be used to secrete an antibacterial substance that ultimately was named penicillin. Before penicillin production, people were vulnerable to various infections such as rheumatic fever, gonorrhea, and pneumonia. Fleming took this challenge, and through a Petri dishes containing Staphylococcus colonies, he found substances that were capable of destroying certain bacteria like meningococcus and streptococcus (Bennett and Chung, 2001, p.163-184). This became a breakthrough in penicillin production in the late 1920s.
Although he was not among the first to use penicillin as a medicine, he successfully improved production and distribution of penicillin globally. Up to date, there are over 60 antibiotics that originated from penicillium mold and helps in fighting bacteria, microbes, and fungi in human bodies. In 1929, Fleming published his discoveries in the British Journal of Experimental Pathology which explained the therapeutic benefits of penicillin. In the subsequent years, several bacteriologists that included Harold Raistrick enhanced the research of penicillin while others like Edward Abraham and Ernst chain was involved in mass production of penicillin (Florey, 1946, p.160-171).
Penicillin Production in the United States During Second World War
Before the second world war, United States became engaged in the production of substantial amounts of penicillin. Researchers used a large quantity of penicillin to conduct mass clinical trials to confirm its effectiveness in diagnosing several health complications. Howard Florey and other Oxford University researchers were engaged in the study of how penicillin could control Streptococci infection in mice (Zaffiri et al., 2012, p.67-77). The experiment became successful and thus forced them to travel to the US to require the services of the American pharmaceutical industry in the large-scale production of penicillin (Gestrelius, 1979, p.11-45). This move was supported by Norman Heatley (colleague) and Rockefeller Foundation who had a passion for medical improvement.
US pharmaceutical companies led by Lilly, Squibb, and Merck supported Floreys idea of penicillin production. The engaged in a further independent researcher who later resulted in starting of plants that produced large amount of penicillin under OSRD auspices for treatment. Large-scale production of penicillin was boosted by lactose-sucrose substitution that had been used by the Oxford team. Additionally, another breakthrough came through the discovery that corn-steep liquor was capable of producing a ten-fold increase in penicillin yields (Prestidge and Pardee, 1957, p.48). Similarly, multiple laboratories were used to penicillin precursors such as phenylacetic acid to intensify penicillin production. By mid-1942, there was the production of enough penicillin that could serve millions of people (Fuska and Proksa, 1976, p.259-370).
Formation of Penicillin G
Penicillin G became the first form of penicillin to be produced and became the most widely form to be used globally. Ideally, penicillin G was designed to be of the narrow spectrum and was to treat bacteria-caused infections. This antibiotic is administered intramuscularly or intravenously to get it into the bloodstream (Wang and Su, 1990, p.21-35). Penicillin G discovery remains one of the new inventories in history. The drug invention was triggered by a blue-green mold that fell into a surface containing Staphylococcus aureus and immediately formed a clear patch. Fleming observed this unusual reaction and found that the mold was able to produce an antibiotic substance.
After this discovery, he named the antibiotic penicillin and published it for researchers to determine if they could treat certain infections and increase its quantity. However, multiple experiments failed to show its therapeutic value and took over ten years before another great discovery was found. The antibiotic developed by Fleming successfully treated a person with a small cut in the face in 1939, and thus penicillin became recognized as a drug that could save millions of patients. Similarly, penicillin G project of Florey became a top priority in the same year in the US and beer-brewing technology was used to produce moldy liquor to be used in penicillin G production (Hare, 1982. P.1).
After several months of production, various medical firms became engaged in slow purification process that aimed at producing a large quantity of medicinal penicillin G which could be used by the US troops during the second world war. Medical companies in association with government health departments commenced mass production of penicillin G by late 1943 and by early 1944, a substantial number of penicillin G had been manufactured. Interestingly, the success of the drug during the entire second world war led its commercial production. Annual production of Penicillin reached billions of units by 1946 and was made famous by chemists, microbiologists, pharmaceutical manufacturers as well as government agencies (Wainwright, 1987, p.41).
Improvements in Bioreactor Configuration
For the high production of the penicillin, the bioreactor to be used should be of good design. The configuration of bioreactors determines the production of fungal metabolites and cultivation of filamentous fungi. The fermenter is the standard bioreactor for controlling fermenter microorganisms. The configuration of the fermenter being used during the fermentation process is what makes mass production of penicillin successful. Ideally, the primary aim of the fermenter is to provide a conducive and homogeneous environment that allows safe fermentation process (Lemke and Brannon, 1972, p.376-379). Fermenters have continuously been modified to improve penicillin fermentation which is mostly done through deep-tank fermentation.
Improvements are made to make the bioreactor flexible and accommodate expansion of reactors. Mass transfer always occurs while growing aerobic microbes in media hence impellers were designed to enable mixing and bulk flow. In fact, most reactors have been designed to have Rushton Flat-bladed disc turbine to make penicillin fermentation fast. Similarly, bioreactors have been developed to have a pressure vessel design while steam of 120 degrees Celsius is passed through it for about half an hour. Pfizer's company did most developments in bioreactors. Pfizer developed deep-tank fermentation that became a breakthrough for the fermentation process to produce gluconic acid and other penicillin ingredients (Oreshina et al., 1982, p.728-732).
Initially, Pfizer used several 7,500-gallon tanks to produce penicillin, and the subsequent improvements enabled the company surpasses its target of the drug production. The general improvements done on the bioreactors include using modified flasks and seed tanks to propagate a sterile culture of the penicillin mold. Later, huge fermenter tanks were developed to enable growth of the mold for several days. The primary reason behind improvements and design of bioreactors is the limitation at the level of oxygen transfer capacity especially for submerged fermentation (Keyes, 1944, p.610-615). Other aspects that determine bioreactor design are morphology of fungus and the need to have a sterile process or not.
Media for Fermentation
Penicillin production requires various medias proper supply of oxygen, nitrogen, carbon, and Sulphur. These media aids in cell maintenance and growth of microorganisms used in penicillin production. Additionally, elements such as manganese, copper, and cobalt are crucial for the growth of Penicillium chrysogenum microorganism that produces penicillin antibiotics. Production of penicillin requires fermenters supplied with precursors such as organic acids or purine bases to produce metabolites. Selection of media has always been given priority by pharmaceutical companies because it determines the kind of final product formed. The media selected must provide a conducive environment for chemical reactions and should be cost-effective (Martinez-Blanco et al., 1992, p.5474-5481).
Production of penicillin is initiated by both primary and secondary metabolism. Primary metabolism occurs where Penicillium chrysogenum converts glucose into pyruvic acid while producing energy. Secondary metabolism, on the other hand, enables valuable microorganisms to utilize metabolites to kill competitors hence generating an environment for self-propagation. These two levels of metabolism are targeted by a microbiologist to achieve the maximum amount of penicillin antibiotics through fermentation. With all the materials and favorable conditions in place, the process of fermentation is then conducted in stages (Sylvester and Coghill, 1954, p.219-263). Fermentation is done in stages because metabolism takes place at different intervals to ensure maximum production of penicillin production.
The first stage of fermentation is primary metabolism. In this stage, glucose is used to provide the culture with a carbohydrate that ensures maximum growth of microorganisms. Glucose is selected because it enhances metabolism and subsequent growth of useful substances of the fermentation process. The second stage is production stage where the already formed biomass is subjected to several stress conditions that result in the formation of penicillin antibiotic. Furthermore, nitrogen and carbon are minimized at this stage for better yields. This is done by adding lactose to the medium through batch method. Ultimately, little amounts of substrates are added into the reactor for best results of the final product (Cali et al., 2005, p.31-145).
Development of High Yield Strains and Medium Improvements of Penicillin
Pharmaceutical companies and the University of Wisconsin played a crucial role in the development of effective penicillin through developing high yield strains as well as medium enhancements. The research on Penicillium chrysogenum that produces high fields of penicillin was conducted in the 1940s and involved screening several cultures for capabilities of producing penicillin. Ideally, the interest shifted to cultures that were able to provide no pigments but yields a large amount of penicillin. Studies were conducted in departments using pilot plant fermentations and shaken flasks to determine cultures that are superior (Bose, 1952, p.349-355). Additionally, the process of determining high-yielding medium was conducted through submitting the culture into different mediums.
According to various tests done, researchers found that the penicillin production depended on variations in the quantity of inoculum. High-yielding cultures require 6% volume of inoculum that contains dry mycelium. This substance was found by being inoculated with a high number or a small number of spores depending on th...
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