Production of antibiotics

The production of antibiotics has been widespread since the pioneering efforts of Florey and Chain in 1939. The importance of antibiotics to medicine has led to much research into discovering and producing them.

Identifying useful antibiotics
Despite the wide variety of known antibiotics, less than 1% of antimicrobial agents have any medical or commercial value. The most commonly known antibiotic, Penicillin has a highly selective toxicity and therapeutic index (as eukaryotic animal cells do not contain peptidoglycan, they are usually unaffected by it). This is not so for many antibiotics. Others simply lack advantage over the antibiotics already in use, or have no other practical applications.

In order to identify the useful antibiotics, a process of screening is often employed. Using this method, isolates of a large number of microorganisms are cultured and then tested for production of diffusible products which inhibit the growth of test organisms. However, the majority of the resulting antibiotics are already known and must therefore be disregarded. The remainders 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 being directed towards finding new natural products that inhibit specific targets (e.g. a particular step of a metabolic pathway) on microorganisms, rather than tests to show general inhibition of a culture.

Industrial production techniques
Antibiotics are produced industrially by a 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 levels must be optimal, and are closely monitored and adjusted if necessary. 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 simpler to achieve if the antibiotic is soluble in organic solvent. Otherwise it must first be removed by ion exchange, adsorption or chemical precipitation.

Strains used for production
Microorganisms used in fermentation are rarely identical to the wild type. This is because species are often genetically modified to yield the maximum amounts of antibiotics. Mutation is often used, and is encouraged by introducing mutagens such as ultraviolet radiation, x-rays or certain chemicals. Selection and further reproduction of the higher yielding strains over many generations can raise yields by 20-fold or more. Another technique used to increase yields is gene amplification, where copies of genes coding for proteins involved in the antibiotic production can be inserted back into a cell, via vectors such as plasmids. This process must be closely linked with retesting of antibiotic production and effectiveness.