Biotechnology - Yu.O. Sazykin 2006

Applied Biotechnology
Challenges in the Discovery, Development, and Application of Antibiotics in Medical Practice
Antibiotic Resistance: Strategies and Solutions to Combat Antibiotic Resistance

The need to periodically update Antibiotics used in medicine is driven by the gradual spread of antimicrobial resistance variants throughout the microbial world. The continuous use of a specific antibiotic in clinical practice within a given geographical region over 20—30 years or more leads to a steady increase in the detection of strains resistant to it. Antimicrobial agents used in medical practice do not directly interact with the microbial genome, meaning they are not mutagens.

However, microbial populations do undergo various, albeit rare, "spontaneous" Mutations in individual genes, the causes of which remain unknown. This results in The Emergence of mutants with altered subcellular structures and metabolic irregularities. Normal Cells, shaped by long-term evolution, are well adapted to their natural environment. Mutants are less suited to such conditions and typically disappear after a certain period and A number of generations. Yet, if the environment itself changes and these changes persist over time, mutant microbial strains may prove better adapted to the new conditions, thereby explaining the spread of such diverse antibiotic-resistant forms.

When used massively and continuously, identical antibiotics act as selective factors that drive the Selection of resistant mutant microorganisms. In this scenario, it is precisely the mutants possessing resistance that realize their potential. Original antibiotic-susceptible cultures are deprived of this opportunity, even if their reproduction rate in an antibiotic-free environment exceeds that of mutants. Spontaneous mutations are by no means the sole source of resistance genes.

Producers of certain antibiotics, such as Aminoglycosides, possess Enzymes that modify or transform their own antibiotic molecule, leading to its subsequent inactivation. Genes encoding inactivating Enzymes can be incorporated into the DNA of certain phages, and sometimes into Plasmids, and transferred from producers to the cells of pathogenic and non-pathogenic Bacteria. Thus, the Introduction of resistance genes into pathogenic microorganisms is predetermined by the existence of antibiotic producers themselves within biocenoses.

There is direct evidence that antibiotic resistance genes—and, consequently, the various mechanisms of this resistance—existed prior to the late 1950s, before penicillin, streptomycin, chloramphenicol (levomycetin), and Tetracyclines came into widespread use.

Museum collections of bacterial cultures preserved since the late 19th century and unexposed to antibiotic preparations (these museum cultures are subcultured two to three times a year in specialized sterile hoods with extreme precautions) occasionally contain variants resistant to specific antibiotics. For instance, genes encoding beta-lactamase production have been identified in such cultures.

Further proof of the primordial existence of antibiotic resistance genes was obtained in the 1960s by microbiologists in remote Regions of the planet where local populations had not yet encountered antibiotics (such as the upper reaches of the Amazon and the islands of Polynesia). Although very rarely, strains carrying resistance genes responsible for The production of beta-lactamases or enzymes that inactivate aminoglycoside antibiotics were isolated from the intestinal microflora of indigenous peoples.

All these facts indicate that completely eliminating resistance genes is theoretically impossible, but their frequency of distribution can be minimized. Removing an antibiotic from clinical practice leads to a decrease in the prevalence of genes conferring resistance to it. After a certain period, the antibiotic and its closely related drugs will regain their efficacy and can be reintroduced into medical practice. For example, in the USA, streptomycin—having lost much of its effectiveness—was displaced from clinical practice by gentamicin, amikacin, semisynthetic beta-lactams, and other novel antibiotics. In small towns that are not major transit hubs for large populations, streptomycin recovered its efficacy approximately 20 years after its use was discontinued.

In the Netherlands, The Use of tetracycline in animal husbandry was banned due to the widespread prevalence of tetracycline-resistant Salmonella. Just five years after this ban, the frequency of these bacteria in the country halved, and the efficacy of tetracycline in treating food poisoning cases doubled.

The overall strategy in combating antibiotic resistance may involve the sequential rotation of drugs, with "older" agents being reintroduced into practice after a specified period. Such "cyclical use" will yield the desired results much faster if implemented across large geographical regions.

Currently, the assortment of antibiotics and other antimicrobial agents available in clinical practice does not allow for a sufficiently effective, complete replacement of one antibiotic group with another. However, provided that a series of new antibiotic classes are developed, THE PRINCIPLE OF cyclicity could be successfully implemented. This would lead to a gradual and significant reduction in resistance genes directed against the temporarily retired groups of antimicrobial agents.

Thus, ensuring not only Treatment efficacy but also the restoration of ecological equilibrium within the human microflora requires intensified efforts to discover and develop—via Biosynthesis and organic synthesis—antibiotic agents featuring novel Mechanisms of action.

Control Questions

1. What is the Biological Role of Antibiotics as Secondary metabolites?

2. How does the accumulation of an antibiotic as a target product correlate with biomass accumulation?

3. What are the approaches for generating highly active antibiotic producers?

4. What are the defense mechanisms against their own antibiotics in superproducers?

5. What are the specific Fermentation features of actinomycetes and bacteria (eubacteria) as antibiotic producers?

6. Why do antibiotic prescribing instructions contain References to PBPs2 and PBPs3?

7. What hazards are posed by chromosomal and plasmid resistance?

8. Which antibiotic preparations represent the new generations of Cephalosporins and Penicillins?

9. What is The Mechanism of resistance to aminoglycoside antibiotics?

10. What are the advantages of targeted aminoglycoside transformation, as exemplified by the antibiotic amikacin?

11. What erythromycin analogs that surpass its efficacy against intracellular pathogens are currently known?

12. What are the natural sources of antibiotic resistance genes?

13. What organizational measures limit the spread of antibacterial resistance genes?