Biosynthesis of antibiotics

Three technological approaches to production

In modern practice, there are three main methods for obtaining antimicrobial drugs:

1. Biological synthesis. Used to create natural antibiotics (e.g., penicillin and streptomycin). The method is based on fermentation: specially selected strains of producer microbes are grown under optimal conditions in a liquid nutrient medium. During their vital activity, they release the target antibiotic, which is then thoroughly purified.
2. Biosynthesis with chemical modification. This two-stage approach allows the production of semi-synthetic drugs. At the first stage, the microorganism synthesizes the base natural molecule. At the second stage, under laboratory conditions, the structure of this molecule is modified by attaching or removing specific chemical radicals. The main goal of such transformation is to improve pharmacological characteristics and enhance antimicrobial properties.
3. Chemical synthesis. Represents the complete recreation of a molecule's structure using artificial methods, completely without the participation of living producer microbes. This is how synthetic analogues of natural substances are obtained (e.g., chloramphenicol, also known as levomycetin, is completely identical to the natural antibiotic) or unique synthetic classes.

Main stages of biological synthesis

Industrial production of natural antibiotics is a strict algorithm consisting of several sequential steps:

• Selection of producers. To obtain the most productive strains, induced mutagenesis is applied, and superproducers are engineered using genetic engineering methods.
• Medium preparation. A special liquid nutrient medium is prepared, optimal for the submerged cultivation of a specific microorganism.
• Cultivation. The process takes place in large culture apparatuses (fermenters) using a submerged method, with or without aeration. To direct the cell's metabolic processes exclusively toward the biosynthesis of the desired antibiotic, technologists strictly control and alter environmental conditions (composition, pH level).
• Isolation and purification. The target substance is extracted from the culture liquid using methods of extraction, precipitation, crystallization, recrystallization, or sorption on ion-exchange materials.
• Drying and standardization. The purified drug is dried (using lyophilization or spray drying) and standardized according to the active component content.
• Packaging. For oral administration, drugs are tableted and packaged. For parenteral (injection) use, packaging into vials or ampoules takes place under strict aseptic conditions. If necessary, solutions are dried in freeze-drying units. The process concludes with labeling.

Features of semi-synthetic and synthetic drugs

When creating semi-synthetic antibiotics, chemists preserve the core nucleus of the original natural molecule. A classic example is penicillins. Their base core consists of β-lactam and thiazolidine rings and is called 6-aminopenicillanic acid (6-APA). By itself, 6-APA has extremely low antimicrobial activity. However, attaching a benzyl group to it yields highly active benzylpenicillin. Further replacement of the benzyl residue with other radicals allowed the synthesis of such drugs as methicillin, oxacillin, and ampicillin.

Synthetic drugs are constructed differently. For example, fluoroquinolones were synthesized based on nalidixic acid (a naphthyridine derivative) and oxolinic acid (a quinolone derivative). The addition of a fluorine atom and a piperazine ring to their structure provided the drugs with pronounced activity and a very broad spectrum of action.

Classification by spectrum of activity and origin

According to the breadth of pathogen coverage, drugs are divided into two groups:

• Narrow spectrum of action. Active against a strictly limited number of microorganism species.
• Broad spectrum of action. Destroy a large number of both Gram-positive and Gram-negative bacteria. This group includes tetracyclines, macrolides, and chloramphenicol. Penicillins and aminoglycosides occupy an intermediate position: they act on Gram-negative flora and partially on Gram-positive flora.

According to the method of production (origin), the following are distinguished:

1. Biosynthetic (natural) — metabolic products of bacteria, actinomycetes, or molds (penicillin, streptomycin).
2. Semi-synthetic — natural base with artificially attached radicals (methicillin, oxacillin).
3. Synthetic — completely artificial molecules (fluoroquinolones, chloramphenicol).

Prospects and reasons for searching for new drugs

Science does not stand still. Among promising developments are methods of antibiotic immobilization, the use of genetically modified producers, and further chemical modification of natural molecules.

The constant search for new drugs is driven by three main reasons:

• The emergence of resistant forms of bacteria with prolonged use of existing drugs.
• Initially low sensitivity of certain dangerous pathogens to the agents used.
• The need to expand the scope of antibacterial therapy.

Class and exam questions

What else to study on this topic

• Mechanisms of induced mutagenesis for creating superproducers
• Physicochemical foundations of antibiotic extraction and lyophilization
• Structure of the β-lactam and thiazolidine rings of penicillins
• The problem of antibiotic resistance and ways to overcome it
• Technologies for antimicrobial drug immobilization

Other topics in the "Additional Topics" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.