Production of antibiotics is a naturally occurring event, that thanks to advances in science can now be replicated and improved upon in laboratory settings. Due to the discovery of penicillin by Alexander Fleming, and the efforts of Florey and Chain in 1938, large-scale, pharmaceutical production of antibiotics has been made possible. As with the initial discovery of penicillin, most antibiotics have been discovered as a result of happenstance. Antibiotic production can be grouped into three methods: natural fermentation, semi-synthetic, and synthetic. As more and more bacteria continue to develop resistance to currently produced antibiotics, research and development of new antibiotics continues to be important. In addition to research and development into the production of new antibiotics, repackaging delivery systems is important to improving efficacy of the antibiotics that are currently produced. Improvements to this field have seen the ability to add antibiotics directly into implanted devices, aerosolization of antibiotics for direct delivery, and combination of antibiotics with non antibiotics to improve outcomes. The increase of antibiotic resistant strains of pathogenic bacteria has led to an increased urgency for the funding of research and development of antibiotics and a desire for production of new and better acting antibiotics.
Identifying useful antibiotics
Despite the wide variety of known antibiotics, less than 1% of antimicrobial agents have medical or commercial value. For example, whereas penicillin has a high therapeutic index as it does not generally affect human cells, this is not so for many antibiotics. Other antibiotics simply lack advantage over those already in use, or have no other practical applications. Useful antibiotics are often discovered using a screening process. To conduct such a screen, isolates of many different microorganisms are cultured and then tested for production of diffusible products that inhibit the growth of test organisms. Most antibiotics identified in such a screen are already known and must therefore be disregarded. The remainder must be tested for their selective toxicities and therapeutic activities, and the best candidates can be examined and possibly modified. A more modern version of this approach is a rational design program. This involves screening directed towards finding new natural products that inhibit a specific target, such as an enzyme only found in the target pathogen, rather than tests to show general inhibition of a culture. Research into antibiotic identification has shown the opportunity exists to move away from lawn spotting methodology, a methodology which increases the chances of cross contamination. This new methodology involves using Lactobacillus species and shows a clear zone of inhibition as well as allowing for a determination of minimum inhibitory concentration.
Industrial production techniques
Fermentation Industrial microbiology can be used to produce antibiotics via the process of fermentation, where the source microorganism is grown in large containers (100,000–150,000 liters or more) containing a liquid growth medium. Oxygen concentration, temperature, pH and nutrient are closely controlled. As antibiotics are secondary metabolites, the population size must be controlled very carefully to ensure that maximum yield is obtained before the cells die. Once the process is complete, the antibiotic must be extracted and purified to a crystalline product. This is easier to achieve if the antibiotic is soluble in organic solvent. Otherwise it must first be removed by ion exchange, adsorption or chemical precipitation.
Semi-synthetic A common form of antibiotic production in modern times is semi-synthetic. Semi-synthetic production of antibiotics is a combination of natural fermentation and laboratory work to maximize the antibiotic. Maximization can occur through efficacy of the drug itself, amount of antibiotics produced, and potency of the antibiotic being produced. Depending on the drug being produced and the ultimate usage of said antibiotic determines what one is attempting to produce. An example of semi-synthetic production involves the drug ampicillin. A beta lactam antibiotic just like penicillin, ampicillin was developed by adding an addition amino group (NH2) to the R group of penicillin. This additional amino group gives ampicillin a broader spectrum of use than penicillin. Methicillin is another derivative of penicillin and was discovered in the late 1950s, the key difference between penicillin and methicillin being the addition of two methoxy groups to the phenyl group. These methoxy groups allow methicillin to be used against penicillinase producing bacteria that would otherwise be resistant to penicillin.
Synthetic Not all antibiotics are produced by bacteria; some are made completely synthetically in the lab. These include the quinolone class, of which nalidixic acid is often credited as the first to be discovered. Like other antibiotics before it the discovery of nalidixic acid has been chalked up to an accident, discovered when George Lesher was attempting to synthesize chloroquine. However a recent investigation into the origin of quinolones have discovered that a description for quinolones happened in 1949 and that patents were filed concerning quinolones some 5 years before Lesher's discovery.
… excerpt ends here. Continue reading the full article.
