Antibiotic resistance

Classification and intrinsic resistance

In microbiology, two main types of resistance are distinguished: intrinsic (true) and acquired.

Intrinsic resistance is a stable species trait characteristic of certain families or genera. The main mechanism of such defense is the absence of a "target" for the drug in the bacterial cell. A classic example is bacteria of the genus Mycoplasma. Because they naturally lack a cell wall, they are completely resistant to antibiotics that inhibit its synthesis (penicillins and cephalosporins).

An important role in natural resistance is played by the barrier function of the envelopes, which restricts drug penetration. For example, the outer membrane of Gram-negative bacteria contains small-diameter pores. They physically prevent large-molecular-weight compounds from entering the cell.

Genetic bases of acquired resistance

Acquired resistance relies on the presence of specific genes. There are four main pathways for the emergence and transmission of resistance in a microbial population:

1. Chromosomal mutations. Can be single (only one protein changes) or multiple (an entire set of proteins changes). An example of a multiple mutation is the alteration of penicillin-binding proteins in penicillin-resistant pneumococcus.
2. Transfer of R-plasmids (transmissible). They often encode resistance to multiple antibiotic families simultaneously. Inter-species exchange is possible: the TEM-1 plasmid, which encodes $\beta$-lactamase, is characteristic of Gram-negative Enterobacteriaceae, but is also transmitted to penicillin-resistant gonococci (Neisseria gonorrhoeae) and ampicillin-resistant Haemophilus influenzae (Haemophilus influenzae).
3. Transfer of transposons. Mobile elements ensure gene migration within the cell (between the chromosome and plasmids) and promote both vertical and horizontal transmission of defense.
4. Action of integrons. Consists in the expression of gene cassettes with resistance factors.

Role of antibiotics and selection

The key rule of resistance biology: the drug itself is not the cause of mutations. Genome changes occur spontaneously and independently.

The antibiotic acts as a selection factor. Under its influence, susceptible cells die, while accidentally emerged mutant clones gain an advantage—they survive, actively multiply, and are then transmitted to new hosts (humans or animals). This problem is particularly acute in clinical settings, where the continuous use of drugs leads to the formation of hospital strains causing nosocomial infections. Their distinguishing feature is polyresistance (multidrug resistance).

Biochemical defense mechanisms

Normally, an antibiotic should remain active, penetrate through the envelopes, and bind to the intracellular target. In the case of resistance, the bacterium blocks this process. There are three main defense mechanisms:

• Target modification. The structure of the enzyme changes: it performs its work, but drastically loses the ability to bind to the drug (decreased affinity). The microbe can also trigger a metabolic "shunt"—activate an alternative enzyme that the drug does not affect.
• Target unavailability. Achieved by reducing the permeability of the cell wall/membranes or through the efflux mechanism (efflux) — the active "pushing out" of the penetrated antibiotic.
• Drug inactivation. Bacteria produce enzymes that degrade the drug. The genes for such enzymes are localized both in plasmids and in the chromosome. Main examples: $\beta$-lactamases, aminoglycoside-modifying enzymes, and chloramphenicol acetyltransferase.

Overcoming resistance and combat strategy

The most well-known group of degrading enzymes is $\beta$-lactamases, which break the $\beta$-lactam ring. To neutralize them, pharmacology uses $\beta$-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam). On their own, they have low antibacterial activity, but contain a $\beta$-lactam ring in their structure. Inhibitors bind to bacterial enzymes, "distracting" them and thereby protecting the main drug. For example, clavulanic acid is successfully combined with penicillins (amoxicillin, ticarcillin, piperacillin).

It is impossible to completely stop the emergence of resistance. The main goal of medicine is not to contribute to its spread. To this end, it is necessary to prescribe antibiotics according to strict indications, rotate drugs every 10–15 days of therapy, prioritize narrow-spectrum agents, and limit the use of antibiotics outside of medicine (for example, ban their use in veterinary medicine as growth promoters).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Structure and operational principle of efflux pumps in bacteria
• Classification and clinical significance of $\beta$-lactamases
• The role of transposons and integrons in horizontal gene transfer
• Metabolic shunt as a form of target modification

Other topics in the section "Chemotherapeutic Antimicrobial Drugs"

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